In-body device having a multi-directional transmitter

ABSTRACT

Multi-directional transmitters for in-body devices, such as implantable and ingestible devices, are provided. Aspects of the in-body multi-direction transmitters of the invention include signal transmitters configured to transmit an identifying signal in at least two different directions in an x-y plane. Embodiments of the in-body devices are configured to emit a detectable signal upon contact with a target physiological site. Also provided are methods of making and using the devices of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 U.S.C. §119 (e), this application claims priority to thefiling date of U.S. Provisional Patent Application Ser. No. 60/894,171filed on Mar. 9, 2007 and U.S. Provisional Patent Application Ser. No.60/915,635 filed on May 2, 2007; the disclosures of which applicationsare herein incorporated by reference.

INTRODUCTION

As medical technology advances, many diagnostic and therapeuticactivities are carried out with increasingly small implantable medicalor ingestible medical devices. Implantable and ingestible medicaldevices can be configured to perform a variety of different functions,including but not limited to: diagnostic functions, e.g., where thedevices include one or more sensors; therapeutic functions, e.g., wherethe devices enable therapeutic action, such as delivery of electricalpulse, delivery of a pharmaceutically active agent; etc.

With implantable and ingestible medical and related technologies, thereis always a desire to make the devices smaller, e.g., to provide forincreased ease of use, etc. To decrease size, individual components ofthe devices must be designed with a reduced overall physical size, andyet maintain functionality.

One type of component that is present in many implantable and ingestibledevices is a signal transmitter. There is continued interest in thedevelopment of signal transmitters for in-body devices that haveadequate and reliable functionality and are physiologically compatiblesuch that they can be employed with in-body devices, such as implantableand ingestible devices.

SUMMARY

Multi-directional transmitters for in-body devices, such as implantableand ingestible devices, are provided. Aspects of the in-bodymulti-direction transmitters of the invention include signaltransmitters configured to transmit an identifying signal in at leasttwo different directions in an x-y plane. Embodiments of the in-bodydevices are configured to emit a detectable signal upon contact with atarget physiological site. Also provided are methods of making and usingthe devices of the invention.

The multi-direction transmitters of the invention enable robustdetection of a signal emitted by an in-body device, since thetransmitter of the present invention includes a multi-directionaltransmitter capability, thereby enhancing the likelihood that a signalwill be emitted in a direction that will be detected by a receiver,despite the particular position of the device and transmitter relativeto the receiver when the signal is emitted.

Embodiments of the invention include ingestible event markercompositions having an identifier and a pharmaceutically acceptablecarrier. The identifier is characterized by being activated upon contactwith a target site fluid present at a target site. Aspects of theidentifier include the presence of a multi-directional transmitter. Uponactivation, a signal broadcasted from the identifier may be received byanother device, e.g., a receiver, either inside or near the body, whichmay then record that the pharmaceutical composition has in fact reachedthe target site.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a schematic view of a pill that includes an identifieraccording to an embodiment of the invention.

FIG. 2 provides a schematic view of an identifier according to anembodiment of the invention.

FIG. 3 provides a schematic view of an identifier according to anembodiment of the invention.

FIG. 4 provides a view of an identifier according to an embodiment ofthe invention.

FIG. 5 provides a diagram of a portion of an identifier circuitaccording to an embodiment of the invention.

FIG. 6 provides detail of certain implementations of an electroniccircuit of an embodiment of the invention.

FIGS. 7 to 7H provides detail of certain implementations of anelectronic circuit for controlling a multi-directional transmitteraccording to an embodiment of the invention.

FIGS. 8A-F provide diagrams of a mechanical multi-directionaltransmitter according to one embodiment of the invention.

FIG. 9 provides a diagrammatic, exemplary representation of the pillembodiment as part of system, in accordance with the present invention.

DETAILED DESCRIPTION

Multi-directional transmitters for in-body devices, such as implantableand ingestible devices, are provided. Aspects of the in-bodymulti-direction transmitters of the invention include signaltransmitters configured to transmit an identifying signal in at leasttwo different directions in an x-y plane. Embodiments of the in-bodydevices are configured to emit a detectable signal upon contact with atarget physiological site. Also provided are methods of making and usingthe devices of the invention.

In further describing the invention in greater detail, embodiments ofthe multi-direction transmitters and in-body devices that include thesame are reviewed first, followed by a discussion of systems havingdevices that include the in-body devices, and methods of using suchdevices and systems. Also reviewed in greater detail below are kits thatinclude the in-body devices of the invention.

In-Body Devices Having Multi-Directional Transmitters

As summarized above, the invention provides in-body devices havingmulti-directional transmitters. An in-body device is a device that isconfigured to be used inside of a living body. Examples of in-bodydevices include, but are not limited to: implantable devices, e.g.,implantable therapeutic devices, such as but not limited to stents, drugdelivery devices, orthopedic implants, etc., implantable diagnosticdevices, e.g., sensors, biomarker recorders, etc; and ingestibledevices, e.g., ingestible event markers (e.g., as described in greaterdetail below), etc.

One type of in-body device in which the transmitters of the inventionfind use is an ingestible event marker. For ease of description, thein-body devices of the invention will now be further described in termsof embodiments where the transmitter is part of an identifier of aningestible event marker. However, as indicated above, the transmittersof the invention find use in devices other than ingestible eventmarkers, and therefore transmitters of the invention are not limited tothose configured for use in ingestible event markers (IEM).

The identifier of the IEM compositions is one that generates (i.e.,emits) a detectable signal upon contact of the identifier with a targetphysiological site. The identifiers of the present compositions may varydepending on the particular embodiment and intended application of thecomposition so long as they are activated (i.e., turned on) upon contactwith a target physiological location, e.g., stomach. As such, aningestible event marker may comprise an identifier that emits a signalwhen activated at a target site, e.g. when it contacts a target body(i.e., physiological) site. The identifier may be any component ordevice that is capable of providing a detectable signal followingactivation, e.g., upon contact with the target site. The identifiertherefore comprises a signal generation element, e.g. amulti-directional transmitter. In certain embodiments, the identifieremits a signal once the composition comes into contact with aphysiological target site, e.g., the stomach. Depending on theembodiment, the target physiological site or location may vary, whererepresentative target physiological sites of interest include, but arenot limited to: a location in the gastrointestinal tract, such as themouth, esophagus, stomach, small intestine, large intestine, etc. Incertain embodiments, the identifier is configured to be activated uponcontact with fluid at the target site, e.g. stomach fluid, regardless ofthe particular composition of the target site.

Depending on the needs of a particular application, the signal obtainedfrom the identifier may be a generic signal, e.g., a signal that merelyidentifies that the composition has contacted the target site, or aunique signal, e.g., a signal which in some way uniquely identifies thata particular ingestible event marker from a group or plurality ofdifferent markers in a batch has contacted a target physiological site.As such, the identifier may be one that, when employed with a batch ofunit dosages, e.g., a batch of tablets, emits a signal which cannot bedistinguished from the signal emitted by the identifier of any otherunit dosage member of the batch. In yet other embodiments, theidentifier emits a signal that uniquely identifies that particularidentifier. Accordingly, in certain embodiments the identifier emits aunique signal that distinguishes one class of identifier from othertypes of identifiers. In certain embodiments, the identifier emits aunique signal that distinguishes that identifier from other identifiers.In certain embodiments, the identifier emits a signal that is unique,i.e., distinguishable, from a signal emitted by any other identifierever produced, where such a signal may be viewed as a universally uniquesignal (e.g., analogous to a human fingerprint which is distinct fromany other fingerprint of any other individual and therefore uniquelyidentifies an individual on a universal level). In one embodiment, thesignal may either directly convey information about a given event, orprovide an identifying code, which may be used to retrieve informationabout the event from a database, i.e., a database linking identifyingcodes with compositions.

The identifier may generate a variety of different types of signals,including but not limited to: RF signals, magnetic signals, conductive(near field) signals, acoustic signals, etc. Of interest in certainembodiments are the specific signals described in pending PCTapplication serial no. PCT/US2006/16370 filed on Apr. 28, 2006; thedisclosures of various types of signals in this application beingspecifically incorporated herein by reference. The transmission time ofthe identifier may vary, where in certain embodiments the transmissiontime may range from about 0.1 μsec to about 48 hours or longer, e.g.,from about 0.1 μsec to about 24 hours or longer, such as from about 0.1μsec to about 4 hours or longer, such as from about 1 sec to about 4hours, including about 1 minute to about 10 minutes. Depending on thegiven embodiment, the identifier may transmit a signal once or transmita signal two or more times, such that the signal may be viewed as aredundant signal.

The identifiers may vary depending on the particular embodiment andintended application of the composition so long as they are activated(i.e., turned on) upon contact with a target physiological location,e.g., stomach. As such, the identifier may be an identifier that emits asignal when it contacts a target body (i.e., physiological) site. Inaddition or alternatively, the identifier may be an identifier thatemits a signal when interrogated after it has been activated. Identifiercomponents of embodiments of the invention have: (a) an activationcomponent; and (b) a signal generation component, where the signalgeneration component is activated by the activation component to producean identifying signal, e.g., as described above.

The activation component is a component that activates the signalgeneration element of the identifier to provide a signal, e.g., byemission or upon interrogation, following contact of the compositionwith a target physiological site of interest, such as the stomach. Asreviewed in co-pending PCT application serial no. PCT/US2006/016370,activation of the identifier may be achieved in a number of differentways, where such approaches include, but are not limited to: batterycompletion, battery connection, etc. The different activation approachesdisclosed in this co-pending application may be readily adapted toprovide activation, as described herein, and as such are hereinincorporated by reference in their entirety.

Embodiments of activation elements based on battery completion formatsemploy in body battery sources of the invention, where when activatedthe in-body batter power source includes, a cathode, an anode, and anelectrolyte. In such embodiments, when the cathode and anode come intocontact with stomach fluid, the stomach fluid acts as the electrolytecomponent of the battery, such that the added component of the stomachfluid thus completes the battery.

In certain embodiments, the battery that is employed is one thatcomprises two dissimilar electrochemical materials which constitute thetwo electrodes (e.g., anode and cathode) of the battery. When theelectrode materials come in contact with the body fluid, such as stomachacid or other types of fluid (either alone or in combination with adried conductive medium precursor), a potential difference, i.e., avoltage, is generated between the electrodes as a result of therespective oxidation and reduction reactions occurring at the twoelectrodes (such that a voltaic cell or battery is produced).Accordingly, in embodiments of the invention, power sources areconfigured such that when the two dissimilar materials are exposed tothe target site, e.g., the stomach, the digestive tract, etc., a voltageis generated. The two dissimilar materials in an electrolyte are atdifferent potentials. In certain of these embodiments, the in-bodybattery power source may be viewed as a power source that exploitselectrochemical reaction in an ionic solution such as gastric fluid,blood, or other bodily fluids and some tissues.

The dissimilar materials making up the electrodes can be made of any twomaterials appropriate to the environment in which the identifier will beoperating. The active materials are any pair of materials with differentelectrochemical potentials. For instance, in some embodiments where theionic solution comprises stomach acids, electrodes may be made of anoble metal (e.g., gold, silver, platinum, palladium or the like) sothat they do not corrode prematurely. Alternatively, the electrodes canbe fabricated of aluminum or any other conductive material whosesurvival time in the applicable ionic solution is long enough to allowthe identifier to perform its intended function. Suitable materials arenot restricted to metals, and in certain embodiments the pairedmaterials are chosen from metals and non-metals, e.g., a pair made up ofa metal (such as Mg) and a salt (such as CuI). With respect to theactive electrode materials, any pairing of substances—metals, salts, orintercalation compounds—with suitably different electrochemicalpotentials (voltage) and low interfacial resistance are suitable.

A variety of different materials may be employed as the batteryelectrodes. In certain embodiments, electrode materials are chosen toprovide for a voltage upon contact with the target physiological site,e.g., the stomach, sufficient to drive the signal generation element ofthe identifier. In certain embodiments, the voltage provided by theelectrode materials upon contact of the metals of the power source withthe target physiological site is 0.001 V or higher, including 0.01 V orhigher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5volts or higher, and including 1.0 volts or higher, where in certainembodiments, the voltage ranges from about 0.001 to about 10 volts, suchas from about 0.01 to about 10 V.

Materials and pairings of interest include, but are not limited to thosereported in Table 1 below.

TABLE 1 Anode Cathode Metals Magnesium, Zinc Sodium (†), Lithium (†)Iron and alloys thereof, e.g., Al and Zn alloys of Mg Salts Coppersalts: iodide, chloride, bromide, sulfate, formate, (other anionspossible) Fe³⁺ salts: e.g. orthophosphate, pyrophosphate, (other anionspossible) Oxygen or hydrogen (††) on platinum, gold or other catalyticsurfaces Intercalation Graphite with Li, K, Ca, Vanadium oxide compoundsNa, Mg Manganese oxide (†) Protected anodes: certain high energy anodematerial such as Li, Na, and other alkali metals are unstable in theirpure form in the presence of water or oxygen. These may however be usedin an aqueous environment if stabilized. One example of thisstabilization is the so-called “protected lithium anode” developed byPolyplus Corporation (Berkeley, CA), where a polymer film is depositedon the surface of lithium metal to protect it from rapid oxidation andallow its use in aqueous environment or air ambient. (Polyplus has IPpending on this). (††) Dissolved oxygen can also serve as a cathode. Inthis case, the dissolved oxygen in the bodily fluids would be reduced toOH— at a suitable catalytic surface such at Pt or gold. Also of interestdissolved hydrogen in a hydrogen reduction reaction.

In certain embodiments, one or both of the metals may be doped with anon-metal, e.g., to enhance the voltage output of the battery.Non-metals that may be used as doping agents in certain embodimentsinclude, but are not limited to: sulfur, iodine and the like.

In certain embodiments, the electrode materials are cuprous iodine (CuI)or cuprous chloride (CuCl) as the cathode and magnesium (Mg) metal ormagnesium alloy as the anode. Embodiments of the present invention useelectrode materials that are not harmful to the human body.

Depending on the particular embodiment, the cathode and anode may bepresent on the same support or different supports, e.g., where two ormore different supports are bonded together to produce the batterystructure, e.g., as is present in a “flip-chip” embodiment. Similarly,the number of cathodes and anodes in a given battery may vary greatlydepending on the embodiment, e.g., where a given embodiment may includea single battery having one anode and cathode, a single battery havingmultiple anodes and/or cathodes, or two or more distinct batteries eachmade up of one or more cathodes and/or anodes. Battery configurations ofinterest include, but are not limited to, those disclosed in PCTapplication serial no. PCT/US2006/016370 filed on Apr. 28, 2006 andtitled “Pharma-Informatics System”; PCT application serial no.PCT/US2007/022257 filed on Oct. 17, 2007 and titled “In-vivo Low VoltageOscillator for Medical Devices”; PCT application serial no.PCT/US2007/82563 filed on Oct. 25, 2007 and titled “ControlledActivation Ingestible Identifier”; U.S. patent application Ser. No.11/776,480 filed Jul. 11, 2007 entitled “Acoustic Pharma InformaticsSystem”; PCT/US2008/52845 filed on Feb. 1, 2008 and titled “IngestibleEvent Marker Systems”; PCT/US08/53999 filed Feb. 14, 2008 and titled“In-Body Power Source Having High Surface Area Electrode,” thedisclosures of which applications (and particularly batteryconfigurations disclosed therein) are herein incorporated by reference.

In addition to the activation component, e.g., battery component, asdescribed above, ingestible event markers of the invention include asolid support. The solid support may vary depending on the nature of theIEM. In certain embodiments, the solid support is small, e.g., where itis dimensioned to have a width ranging from about 0.01 mm to about 100mm, e.g., from about 0.1 mm to about 20 mm, including from about 0.5 mmto about 2 mm; a length ranging from about 0.01 mm to about 100 mm,e.g., from about 0.1 mm to about 20 mm, including from about 0.5 mm toabout 2 mm, and a height ranging from about 0.01 mm to about 10 mm,e.g., from about 0.05 mm to about 2 mm, including from about 0.1 mm toabout 0.5 mm. The solid support element may take a variety of differentconfigurations, such as but not limited to: a chip configuration, acylinder configuration, a spherical configuration, a disc configuration,etc, where a particular configuration may be selected based on intendedapplication, method of manufacture, etc. While the material from whichthe solid support is fabricated may vary considerably depending on theparticular device for which the device is configured for use, in certainembodiments the solid support is made up of a semiconductor material,e.g., silicon.

In certain embodiments, the solid support is a semiconductor supportthat includes one or more circuit elements, where in certain embodimentsthe support is an integrated circuit. When present, integrated circuitsinclude a number of distinct functional blocks, i.e., modules. Within agiven solid support, at least some of, e.g., two or more, up to andincluding all of, the functional blocks, e.g., power source, processor,transmitter, etc., may be present in a single integrated circuit. Bysingle integrated circuit is meant a single circuit structure thatincludes all of the different desired functional blocks for the device.In these embodiments, the integrated circuit is a monolithic integratedcircuit (also known as IC, microcircuit, microchip, silicon chip,computer chip or chip) that is a miniaturized electronic circuit (whichmay include semiconductor devices, as well as passive components) thathas been manufactured in the surface of a thin substrate ofsemiconductor material. The integrated circuits of certain embodimentsof the present invention may be hybrid integrated circuits, which areminiaturized electronic circuits constructed of individual semiconductordevices, as well as passive components, bonded to a substrate or circuitboard.

In addition to the activation component of the identifier, describedabove, identifiers of the invention also include a signal generationcomponent. The signal generation component of the identifier element isa structure that, upon activation by the activation component, emits adetectable signal, e.g., that can be received by a receiver, e.g., asdescribed in greater detail below. The signal generation component ofcertain embodiments can be any convenient device that is capable ofproducing a detectable signal and/or modulating transduced broadcastpower, upon activation by the activation component. Detectable signalsof interest include, but are not limited to: conductive signals,acoustic signals, etc. As reviewed above, the signals emitted by thesignal generator may be generic or unique signals, where representativetypes of signals of interest include, but are not limited to: frequencyshift coded signals; amplitude modulation signals; frequency modulationsignals; etc.

In certain embodiments, the signal generation element includescircuitry, as developed in more detail below, which produces orgenerates the signal. The type of circuitry chosen may depend, at leastin part, on the driving power that is supplied by the power source ofthe identifier. For example, where the driving power is 1.2 volts orabove, standard CMOS circuitry may be employed. In other embodimentswhere the driving power ranges from about 0.7 to about 1.2 V,sub-threshold circuit designs may be employed. For driving powers ofabout 0.7 V or less, zero-threshold transistor designs may be employed.

In certain embodiments, the signal generation component includes avoltage-controlled oscillator (VCO) that can generate a digital clocksignal in response to activation by the activation component. The VCOcan be controlled by a digital circuit, which is assigned an address andwhich can control the VCO with a control voltage. This digital controlcircuit can be embedded onto a chip that includes the activationcomponent and oscillator. Using amplitude modulation or phase shiftkeying to encode the address, an identifying signal is transmitted.

As summarized above, the signal generation component of the identifierincludes a multi-directional transmitter, which may serve as a distincttransmitter component that serves to transmit the generated signal to aremote receiver, which may be internal or external to the patient, asreviewed in greater detail below. The multi-directional transmitter mayalso function as a signal receiver, and in certain embodiments may haveboth transmitter and receiver functionality, such that it is atransceiver. The transmitter may take a number of differentconfigurations, e.g., depending on the type of signal that is generatedand is to be emitted. In certain embodiments, the transmitter is made upof one or more electrodes.

Aspects of the identifier components include the multi-directionaltransmission capability of the identifier, such that the identifier maybe viewed as a multi-directional transmission identifier. By“multi-directional” is meant two or more directions, such as three ormore directions, including four or more directions, such as five or moredirections, etc., where the different directions of transmission may bein a single plane or in two or more different planes, e.g., to providefor three-dimensional transmission. In certain embodiments theidentifier is configured to transmit an identifying signal in at leasttwo or three different directions in a single plane, e.g. an x-y plane.In certain embodiments, the identifier is configured is configured totransmit an identifying signal in at least two or three differentdirections in each of two or more different planes, e.g. two or more x-yplanes. The multi-directional transmission may operate in a variety ofdifferent formats, including but not limited to electrical formats,physical formats, etc.

As summarized above, aspects of the invention include identifiers thathave multi-directional signal transmission capability. Accordingly, thesignal generation element is configured to provide for multi-directionalsignal transmission. The signal generation composition may have anintegrated or a distinct transmitter component that serves to transmitthe generated signal in a multi-directional manner to a remote receiver,which may be internal or external to the patient, as reviewed in greaterdetail below.

The transmitter component may take a number of different configurations,e.g., depending on the type of signal that is generated and is to beemitted. In certain embodiments, the transmitter component is made up ofthree or more transmission elements, e.g., electrodes, where theelectrodes may be coupled to antenna elements, e.g., wires, wheredesired. In certain embodiments, the signal is transmitted either by oneor two electrodes, which may or may not be part of an antenna, e.g.,coupled to a wire. Accordingly, the multidirectional transmitter may bea monopole or dipole transmitter. In certain embodiments, thetransmitter only requires one diode drop of power. In some embodiments,the transmitter unit uses an electric dipole or electric monopoleantenna to transmit signals.

FIG. 1 provides a representation of a pharma-informatics enabled pillcomposition 10 having an identifier 11 present in a pharmaceuticalvehicle/active agent pill 12. Identifier 11 includes logic element 15and transmitter element 16. In order to provide multi-directional signaltransmission, transmitter element 16 may include 3 or more transmissionelements, e.g., in the form of electrodes which may or may not becoupled to an antenna element (such as a wire), including four or moretransmission elements, such as five or more transmission elements, sixor more transmission elements, etc., where the embodiment shown in FIG.1 has three electrodes, i.e., E₀, E₁ and E₂.

FIG. 2 provides another view of an embodiment of an identifier 50according to the invention. In the identifier 50 shown in FIG. 2,substrate 55 has a hexagonal surface. Signal generation component, e.g.,multi-directional transmitter 70, includes circuitry 51, which may beelectrically coupled to additional electronic circuitry, such as logicelement 15, as shown in FIG. 1, to produce or generate the signalemitted by the multi-directional transmitter 70. The multi-directionaltransmitter 70 also includes signal transmission electrodes 52, 53 and54 that are coupled to respective outputs 51 a, 51 b, and 51 c. Box 71represents the activation components described above, which activate thesignal generation component, e.g., multi-directional transmitter 70 oradditional circuitry to produce or generate the signal emitted by themulti-directional transmitter 70 using the signal transmissionelectrodes 52, 53 and 54. The signal transmission electrodes 52, 53 and54 are located at every other corner of the hexagonal surface ofsubstrate 55, and are designated as signal transmission electrodes E₀,E₁ and E₂, i.e., 52, 53 and 54, respectively. The transmissionelectrodes are arranged on the surface in a non-linear arrangement thatis sufficient to provide for multi-directional transmission of anidentifying signal during use.

FIG. 3 provides a view of another embodiment of a signal generationelement. In the embodiment shown in FIG. 3, signal generation component,e.g., multi-directional transmitter 70, includes control circuitry 51which may be electrically coupled to additional electronic circuitry,such as logic element 15, as shown in FIG. 1, to produce or generate thesignal emitted by the multi-directional transmitter 70. Themulti-directional transmitter also includes signal transmission elements52, 53 and 54 coupled to respective outputs 51 a, 51 b, and 51 c. Thesignal transmission elements include electrodes 52, 53 and 54 coupled toantennae 58, 56 and 57, respectively. Each antenna may vary in length,ranging in certain embodiments from 100 μm to 10 cm, such as from 1 mmto 2 cm, including from 2 mm to 5 mm. The antennas, when present, mayhave a variety of different configurations ranging from linear tonon-linear. The antennas may be configured such that they are coplanarwith the substrate surface or extend in three dimensions relative to thesubstrate surface of the identifier. For example, FIG. 4 shows anembodiment of an identifier where antenna elements extend in threedimensions relative to the substrate surface. In FIG. 4, substrate 55includes three different electrodes, 52, 53 and 54, coupled to curvedantenna elements 58, 56 and 57, respectively. Each antenna element iscurved to extend upward from the substrate surface.

Depending on a given embodiment, the signal may or may not be modulated.For example, in certain embodiments the frequency of the signal may beheld constant. In yet other embodiments, the signal may be modulated insome manner, e.g., via carrier based modulate schemes, ultra-wide band(or time domain based) modulation schemes, etc. Information can beencoded in various ways, generally by modulating (varying) some propertyof the transmitted signal, such as frequency, amplitude, phase, or anycombination thereof. Modulation techniques known in the art may beemployed.

In general, information can be transmitted using analog or digitaltechniques. “Analog techniques” refers generally to instances in whichthe modulated property is varied in different degrees, with the degreeof variation being correlated to a value representing the information tobe transmitted. For instance, an oscillator can be designed to operateover some range of frequencies. “Digital techniques” refers generally toinstances in which the information to be transmitted is represented as asequence of binary digits (bits), and the signal is modulated based onthe bit stream. For instance, an oscillator can be designed to operateat least two different frequencies, with one frequency corresponding tobit value 0 and another frequency corresponding to bit value 1. Inembodiments of the present invention, either analog techniques, digitaltechniques, or a combination thereof can be used to transmitinformation. In addition, various types of modulation may beimplemented. For instance, in one embodiment, frequency modulation isused. An oscillator can be a voltage-controlled oscillator (VCO), anoscillator circuit in which the oscillation frequency depends on anapplied voltage. Control logic can supply an appropriate voltage (e.g.,reflecting the value of the measurement data, M), and the frequency ofthe signal indicates the value of the data. In another embodiment,amplitude modulation is used; for instance, the amplitude of the drivingsignals φ and /φ can be varied, or the positive and negative rails ofthe driver circuit (e.g., V+ and V−) can be varied to control theamplitude. In another embodiment, phase modulation is used. Forinstance, in digital signal transmission, one phase corresponds to bitvalue 0, an opposite phase corresponds to bit value 1, and the phaseshifts represent transitions. An oscillator can include a switch circuitthat either directly connects or cross-connects the driving signals φand /φ to the inputs of a driver circuit.

In some embodiments, the transmitter may transmit a “packet” thatincludes a unique identifier for the identifier, which in turn is forthe composition with which the identifier is associated. The uniqueidentifier may also provide information from the remote device (e.g.,the identity of the active agent (i.e., annotation information)). Othertechniques for distinguishing different signals may also be used,including: operating different transmitters in different frequencybands, allowing each transmitter to be identified by its frequencyand/or configuring different transmitters to transmit at different (andknown) times, allowing the transmitter to be identified by when ittransmits.

In certain embodiments, the signal generation component includes avoltage-controlled oscillator (VCO) that can generate a digital clocksignal in response to activation by the activation component. The VCOcan be controlled by a digital circuit, which is assigned an address andwhich can control the VCO with a control voltage. This digital controlcircuit can be embedded onto a chip that includes the activationcomponent and oscillator. Using amplitude modulation or phase shiftkeying to encode the address, an identifying signal is transmitted.

In certain embodiments, the signal generation element includescircuitry, as developed in more detail below, which produces orgenerates the signal that is then transmitted in a multi-directionalmanner as described above. The type of circuitry chosen may depend, atleast in part, on the driving power that is supplied by the power sourceof the identifier. For example, where the driving power is 1.2 volts orabove, standard CMOS circuitry may be employed. In other embodimentswhere the driving power ranges from about 0.7 to about 1.2 V,sub-threshold circuit designs may be employed. For driving powers ofabout 0.7 V or less, zero-threshold transistor designs may be employed.

FIG. 5 is a block diagram of one embodiment of electronic circuit 20found in a signal generation element of an identifier according to theinvention, showing in more detail the signal generation 15 and signaltransmission 16 functional blocks of FIG. 1. In this embodiment, circuit20 is a transmitter unit that sequentially transmits a predeterminedseries of address (identifier) bits using frequency shift keying, with afirst oscillation frequency corresponding to bit value 0 and a secondoscillation frequency corresponding to bit value 1. As described above,activation component (not shown) supplies power to circuit 20. The poweris supplied to an oscillator 25, a counter 26, a readout circuit 27, andan electrode driver 28 that drives transmitter electrodes 29A, 29B and29C to transmit the signal. Oscillator 25 may be of generallyconventional design (e.g., a ring oscillator). Oscillator 25 generates adriving signal φ that oscillates between high and low voltage levels andan inverted driving signal /φ that is opposite in phase to drivingsignal φ. In one embodiment, oscillator 25 is a voltage-controlledoscillator (VCO) with an oscillation frequency that depends on a controlvoltage provided on a signal path 25A. Counter 26 counts theoscillations of driving signals φ and /φ and provides the current countto readout circuit 27. In one embodiment, counter 26 is an eight-bitcounter of generally conventional design; other types of counters(including counters with different widths) may also be used. Readoutcircuit 27 is configured with a set of address (identifier) bits 27Athat are advantageously fixed, e.g., at the time circuit 20 isfabricated. As noted above, the bits can be unique to a particularinstance of a given pharmaceutical composition or common to a lot ofcompositions (e.g., pills) fabricated under the same conditions orcommon to all pills containing a particular pharmacological agent.Address bits can be stored in nonvolatile storage circuits of generallyconventional design, and any number of address bits (e.g., 8, 16, 32,48, etc.) may be provided. As such, the signal may be 8-bit or longer,e.g., 16-bit or longer, such as 32-bit or longer, as desired. Readoutcircuit 27 generates an oscillator control signal (e.g., a voltage) online 25A that controls the frequency of VCO 25. In one embodiment,readout circuit 27 is configured to select a current address bit, e.g.,based on the current count provided by counter 26, and to generate acontrol signal on signal line 25A that selects a frequency correspondingto the value of that bit. After some number of cycles (as determined bycounter 26), readout circuit 27 selects the next address bit andgenerates the corresponding control voltage on signal line 25A. Variousfrequencies may be used to represent the address bit values “1” and “0.”In one embodiment, frequencies of 100 kHz and 200 kHz may be used torepresent values “0” and “1,” respectively. Other values (e.g., 1 MHzand 2 MHz or 1 kHz and 5 kHz) may also be used. The chosen frequenciesadvantageously are well below the absorption modes of human tissues,which are typically above 400 MHz. As described above, VCO 25 generatescomplementary signals φ, /φ that oscillate at a frequency determined bythe control signal on signal line 25A. The signals φ, /φ are used tocontrol an electrode driver 28. In one embodiment, the collector isconfigured to log the received address (identifier) and the time ofreceipt. The data collector can also be configured to retransmit thisinformation to an external device, either in real time or while thepatient is in a medical facility. It will be appreciated that thetransmitter described herein is illustrative and that variations andmodifications are possible. For instance, other encoding schemes couldbe used to transmit the data; in one such embodiment, phase shift keyingrather than frequency keying is used. In some embodiments, multipleaddress bits can be encoded into a single symbol that is transmittedusing various keying schemes known in the art.

FIG. 6 shows the detail of one implementation of an electronic circuitthat can be employed in an identifier according to the presentinvention. On the left side are the two battery electrodes, metal 1 andmetal 2 (32 and 33). These metals, when in contact with an electrolyte(produced upon contact with target site fluid, either alone or incombination with dried conductive medium precursor, as reviewed above),form a battery that provides power to an oscillator 61, in this caseshown as a schematic. The metal 1 32 provides a low voltage, (ground) tothe oscillator 61. Metal 2 33 provides a high voltage (V_(high)) to theoscillator 61. As the oscillator 61 becomes operative, it generates aclock signal 62 and an inverted clock signal 63, which are opposites ofeach other. These two clock signals go into the counter 64 which simplycounts the number of clock cycles and stores the count in a number ofregisters. In the example shown here, an 8 bit counter is employed.Thus, the output of counter 64 begins with a value of “00000000,”changes to “00000001” at the first clock cycle, and continues up to“11111111.” The 8-bit output of counter 64 is coupled to the input of anaddress multiplexer (mux) 65. In one embodiment, mux 65 contains anaddress interpreter, which can be hard-wired in the circuit, andgenerates a control voltage to control the oscillator 61. Mux 65 usesthe output of counter 64 to reproduce the address in a serial bitstream, which is further fed to the signal-transmission driving circuit.Mux 65 can also be used to control the duty-cycle of the signaltransmission. In one embodiment, mux 65 turns on signal transmissiononly one sixteenth of the time, using the clock counts generated bycounter 64. Such a low duty cycle conserves power and also allows otherdevices to transmit without jamming their signals. The address of agiven chip can be 8 bits, 16 bits or 32 bits. Typically, more than 8bits will be used in a product because there are so many different typesof pharmaceuticals. Each pharmaceutical will have its own specificaddress.

As reviewed above, the signal may vary significantly. In certainembodiment, the signal is a phase-shift-keyed signal. For example, thesignal may be a 32 bit code that is phase-shift-keyed as a stream ofsub-bits. In such embodiments, each sub-bit in the encoded bit streammay be implemented as a specific sequence of driver logic vectors in 16different ways: 4 different drive patterns and 4 different data rates.For example, the code may consist of a 16-bit clock signal, a 4-bitpreamble, an 8-bit payload, and a 4-bit disable sequence when all of theelectrodes are off. 4 codes possible are:

Code Designation Bit Sequence 0 0000 0000 0000 1010 1100 1100 (Z)x104 10000 0000 0000 1010 0001 0001 (Z)x104 2a 0000 0000 0000 1010 1010 0101(Z)x104 2b 0000 0000 0000 1010 1110 1010 (Z)x104In one bipolar coding scheme, the encoding scheme maps a code bit to anencoded sub-bit sequence, with the sequence repeated 16 times for a codebit 1, and the negation of the sequence repeated 16 times for a code bit0

Encoding Scheme Code Bit 0 Code Bit 1 PSK-16 CCCCCCCCCCCCCCCC = (C) × 16~(CCCCCCCCCCCCCCCC) = (~C) × 16The encoded sub-bit stream may be modulated to the 3 electrodes in 16different ways sequentially, which are listed below:Monopole-2

Electrode C E0 0011 E1 0011 E2 0011 CLK 1010E0/E1-2

Electrode C E0 0011 E1 1100 E2 ZZZZ CLK 1010E0/E2-2

Electrode C E0 0011 E1 ZZZZ E2 1100 CLK 1010E1/E2-2

Electrode C E0 ZZZZ E1 0011 E2 1100 CLK 1010Beacon-3

Electrode C E0 11ZZ00 E1 0011ZZ E2 ZZ0011 CLK 101010E0/E1-4

Electrode C E0 00001111 E1 11110000 E2 ZZZZZZZZ CLK 10101010E0/E2-4

Electrode C E0 00001111 E1 ZZZZZZZZ E2 11110000 CLK 10101010E1/E2-4

Electrode C E0 ZZZZ E1 0000 E2 1111 CLK 1010Beacon-6

Electrode C E0 1111ZZ0000ZZ E1 00ZZ1111ZZ00 E2 ZZ0000ZZ1111 CLK101010101010E0/E1-6

Electrode C E0 000000111111 E1 111111000000 E2 ZZZZZZZZZZZZ CLK101010101010E0/E2-6

Electrode C E0 000000111111 E1 ZZZZZZZZZZZZ E2 111111111111 CLK101010101010E1/E2-6

Electrode C E0 ZZZZZZZZZZZZ E1 000000111111 E2 111111000000 CLK101010101010Beacon-12

Electrode C E0 11111111ZZ0000000000ZZ11 E1 0000ZZ1111111111ZZ000000 E2ZZ0000000000ZZ1111111111 CLK 101010101010101010101010E0/E1-12

Electrode C E0 000000000000111111111111 E1 111111111111000000000000 E2ZZZZZZZZZZZZZZZZZZZZZZZZ CLK 101010101010101010101010E0/E2-12

Electrode C E0 000000000000111111111111 E1 ZZZZZZZZZZZZZZZZZZZZZZZZ E2111111111111000000000000 CLK 101010101010101010101010E1/E2-12

Electrode C E0 ZZZZZZZZZZZZZZZZZZZZZZZZ E1 000000000000111111111111 E2111111111111000000000000 CLK 101010101010101010101010On a particular chip with a particular code, the different modulationschemes are output in sequence. The code may be output in each of the 16modulation schemes, with a dormant state, where all the outputs aredisabled, for a set duration between. The output sequence may be:Monopole-2E0/E1-2E0/E2-2E1-E2-2Beacon-3E0/E1-4E0/E2-4E1-E2-4Beacon-6E0/E1-6E0/E2-6E1-E2-6Beacon-12E0/E1-12E0/E2-12E1-E2-12

The present invention also allows the possibility that, whereappropriate, each pharmaceutical batch can be provided with a batchspecific address. This allows identification of where the pill was made,when the pill was made, and in what batch it was made. In some cases,each pill will have a unique identifier. This would be particularlyuseful when drugs are more likely to be subsequently stolen or usedillicitly, and thus should be tracked, or where questions ofcontamination may arise.

According to one embodiment, mux 65 produces a control voltage, whichencodes the address serially and is used to vary the output frequency ofoscillator 61. By example, when the control voltage is low, that is,when the serial address bit is at a 0, a 1 megahertz signal is generatedby the oscillator. When the control voltage is high, that is, when theaddress bit is a 1, a 2 megahertz signal is generated the oscillator.Alternately, this can be 10 megahertz and 20 megahertz, or a phase shiftkeying approach where the device is limited to modulating the phase. Thepurpose of mux 65 is to control the frequency of the oscillator or an ACalternative embodiment of the amplified signal of oscillation.

The outputs of mux 65 are coupled to electrode drive 66 having at leastthree signal transmission elements, e.g., electrodes (shown in thefigure as E₀, E₁ and E₂) which can drive the signal transmission elementin a variety of formats, e.g., monopole, dipole, etc., to provide amultidirectional transmission of the identifying signal. In this manner,the device broadcasts the sequence of 0's and 1's which constitute theaddress stored in mux 65. The address (i.e., identifying signal) may bebroadcast repeatedly, as desired. Other configurations for the signalgeneration component are of course possible.

Other configurations of interest include, but are not limited to: thosedescribed in copending PCT application serial no. PCT/US2006/016370; thedisclosure of which is herein incorporated by reference.

As summarized above, the multi-directional transmitter component of theidentifier is configured to transmit an identifying signal in multipledirections. As used herein, the term “multi-directional” means that thesignal is at least transmitted in three different directions in a givenplane. For example, the signal is transmitted in a first, second andthird direction in a given x-y plane, such as a plane in which all thesignal generation elements or a portion of thereof lie. In suchembodiments, the magnitude of the angle between two different adjacentdirections may vary, where it may range from 10 to 200°, such as from 50to about 150°, e.g., 120°.

The identifier comprising the transmitter may be configured to transmitthe signal simultaneously from each distinct signal transmissionelement, or be configured to sequentially transmit the signal from eachsignal transmission element. In the latter embodiment, the transmittermay be configured to transmit the signal sequentially from the signaltransmission elements in a manner sufficient to provide formulti-directional transmission of the signal over a given period oftime, e.g., as described above. For example, the identifier comprisingthe transmitter can be configured to sequentially transmit from at leastthree different transmission elements to transmit an identifying signalin more than one direction over a given time period.

For example, in the embodiment shown in FIG. 2, the identifier includesthree different electrodes as transmission elements, i.e., E₀ (52), E₁(53) and E₂ (54). The transmission elements are positioned with an angleθ of 120° between each pair of transmission elements. As reviewed above,angle θ may vary, and in certain embodiments ranges from 10 to 200°,such as from 50 to about 150°. The transmission elements may bedescribed as first, second and third transmission elements. Where thetransmitter is operated in a sequential transmission dipole format, twoof the three electrodes are employed as a pair of transmissionelectrodes at any given time in the sequence. As such, the identifiermay be configured to transmit an identifying signal using the followingsequence of the transmission elements: the first and second transmissionelements; the second and third transmission elements; and the third andfirst transmission elements. In this manner, the signal is sequentiallybroadcast in multiple directions as denoted by arrows 59A, 59B and 59Cin the direction indicated by arrow 59D in FIG. 2.

In the sequential embodiments of the invention, some of which areillustrated in FIG. 2, the transmitter can be configured to sequencethrough the different transmission elements substantially continuously,such that their is little, if any time, between transmissions of theidentifying signal from any two adjacent transmission elements. In suchembodiments, any time delay, if present, will not exceed 10 minutes,such as 100 ms. In yet other embodiments, a time delay is providedbetween transmissions from different transmission elements in thesequence, such that the sequential transmission of the identifyingsignal is intermittent. The time delay in such embodiments may vary, andin certain embodiments ranges from 1μ to 10 minutes, such as from 10 msto 10 seconds.

A variation of the sequential dipole transmission format illustrated inFIG. 2 is shown in FIG. 4. In FIG. 4, a transmission element, i.e., 76,75 and 74, serves as a cathode with a common anode 72 present on theunderside of the substrate. In this manner, during transmission currentflows between a given transmission element and the common anode over anextended path, e.g., see dashed line 78, which provides for transmissionof the signal in three dimensional space.

Where sequential transmission is employed, the transmitter may beconfigured to transmit a complete identifying signal from a firsttransmission element before moving on to a second transmission element.As such, a transmission event from a transmission element includestransmission of a complete signal from the element, before moving on totransmit the signal from another transmission element.

In yet other embodiments, the transmitter may be configured tosequentially transmit only a portion, e.g., a bit, of an identifyingsignal from a given element before moving on to the next element. Assuch, the first portion of a signal will be transmitted from all thetransmission elements and then the next portion of the signal will betransmitted from all the transmission elements and so on, until thecomplete identifier signal has been intermittently or sequentiallytransmitted (e.g., bit by bit) from each of the transmission elements.

Where the signal is sequential broadcast in multiple directions, thesignal may be broadcast once in each direction or several times in eachdirection, such that the sequential transmission is cycled 2 or moretimes, e.g., 3 or more times, 4 or more times, 5 or more times, 10 ormore times, as desired.

The transmitter may included dedicated circuitry which is configured toprovide for the desired transmission protocol, e.g., sequentialtransmission protocol, as described above. An embodiment of suchcircuitry is illustrated schematically in FIG. 7.

FIG. 7 shows the block diagram detail of one implementation of anelectronic circuit for controlling a multi-directional transmitter thatcan be employed according to the present invention. On the left side isa battery generator 91, as illustrated in FIG. 6, which provides powerto an oscillator 93. The cycle counter 103 generates the frequencycontrol signals 119 to the oscillator 93. The oscillator 93 generatesthe clock signal 95, as shown in FIG. 7A as clock signal 97 and aninverted clock signal 99. The two clock signals are inputs to the cyclegenerator 101, cycle counter 103 and the control electrode drive 105.The cycle generator 101 (detailed in FIG. 7B) generates the cycle signal111 in response to the input signals of xby 113 (count_by1 andcount_by0), and state 115 (state1 and state0) from the cycle counter103. The cycle generator 101 outputs the beacon coding controllersignals 107 and binary coding controller signals 109 to the controlelectrode drive 105 (FIG. 7E control_psk).

In the example shown here, the cycle counter 103 employed in FIG. 7A isa 7-bit cycle counter 94. FIG. 7A shows the cycle counter 94 generatesaddress sub bits 90 (add0, add1, add2, add3, add4, add5, add6). Thecycle counter 94 is coupled with an enable address multiplexer 92. Inone embodiment, shown in FIG. 7D, add0 will take either the 0 or 1 fromeach of the multiplexers 117 and sends it on to the next address string.As the clock goes through and counts, the layout is from left to right,and corresponds to the schematic as top to bottom. The first bit to beread is at the bottom, and the last bit to occur is at the top. Thecycle counter 103 generates the add0 bit, then add2 bit, and so on, as aserial 7-bit stream address_out 96 and the enable_b 124 as inputs to thecontrol_psk 126 shown in FIG. 7A. FIG. 7C shows a detail of the cyclecounter 94, which controls the time multiplexing of each address bit for2, 4, 8 or 16 cycles. The clock cycles are 2, 3, 6, or 12 per clockcycle.

The control_psk 126 detailed in FIG. 7E modulates the phase byphase-shift keying the electrode drive signals. FIG. 7H is an embodimentof a simple binary controller waveform with the output of the electrodedrives E0 98 and an inverse phase E1 100. When the address_out 102 goesfrom 0 to 1, from phase A 120 and phase B 122, then the phase shifts(e.g. electrode drives E0 104 and E1 106), otherwise the frequency isconstant.

As reviewed in FIG. 6, the sub bit sequence of E0 98 and E1 100 cycles,is modulated by phase-shift keying the signals, therefore generating aconstant frequency by just flipping the phase. The binary controllerphase truth table 108 in FIG. 7F shows that going from cycle 0 to 1flips the phase, which is the same as the beacon controller phase truthtable 110 in FIG. 7G. However, the beacon controller is dependent onwhether the cycle count is 3, 6, or 12 for the beacon states. FIG. 7Fshows that count by two CNT2 114 (i.e. 2 clocks per cycle) the phase iscontrolled by the binary controller 116. The binary controller enabletruth table 116 and phase truth table 108 illustrates the logic. Thebinary controller phase truth table 108 and output 118 are similar, inthat for a given state it phase-shifts one of them to be anomaly high,and then other to be anomaly low. By changing which pair of states (i.e.S0 and S1) the polarity changes 112, and then by changing the addressthe phase shifts.

In the beacon states the counts are by 2, 3, 6, or 12, and in the binarystates the counts are by 3, 4, 6 or 12. In a production device there canbe various combinations of the controller states. For example, there canbe one or two controllers, e.g. three beacon states or one beacon statewith three binary states. To have all the various different combinationsis more of a test bed model to demonstrate the various frequencies. Inone embodiment, the same chip can be hardwired for a specific frequency(e.g. frequency 2) and disregard frequencies 1, 3 and 4. In yet otherembodiments, the chip maybe configured by programming. The primaryinformation that can be programmed are the addresses.

The transmitter may be configured such that it mechanically sweepsthrough multiple orientations during signal transmission. Themechanically sweeping multi-directional transmitter provides signaltransmission in multiple directions utilizing as few as two electrodes.This reduces the size, complexity, and power requirements of thetransmitter. The switching circuitry is not required when only twoelectrodes are used to transmit, lessening the complexity of thetransmitter while still providing multi-directional transmission. Inother embodiments, the mechanically sweeping properties can beincorporated into a multi-dimensional transmitter which electricallyswitches through multiple transmit orientations, giving another sourceof multi-directionality.

The transmitter can be located on a flexed body, such that two or moreelectrodes are located along the flexed body and separated from eachother. One of the electrodes can be incorporated into the circuitrywhich drives the transmission, and can include the power source.Alternatively, the circuitry and/or power source can be located at athird location. The two electrodes can be electrically connected by aconductor which is located in or on the surface of the flexed body. Theflexed body can be embedded or placed in the capsule in a twisted and/orbent shape such that the electrodes are aligned in a first orientation.As the pill dissolves, the transmitter body will be allowed to unfurl toa second orientation. During the signal sweeping process, the electrodessweep through many different dipole orientations in three dimensions,allowing the identifier signal to be transmitted in multiple directions.The signal sweeping process may last about 1 second to about 8 hours,more specifically about 30 seconds to about 3 hours, most specificallyabout 10 minutes.

The flexed body can be made of a variety of materials, such as plasticsor metals, that have the desired elastic and shape memory properties. Itis important for the flexed body to be easily twisted and bent into thedesired first configuration, but retain shape memory so that it deploysto a second configuration once released from the encapsulation layer.There are many shape memory alloys known in the art, such as nickeltitanium alloys, which change shape in response to a temperature change.These materials can be used in the flexed body, so that the flexed bodywill return to its memory shape when exposed to the temperature of thebody. In some embodiments, the flexed body can be made of anindigestible material which will pass through the body. Because thetransmitter will be small and in many cases flexible, it will passthrough the body without harmful effects. In other embodiments, theflexed body can be made of a digestible material, which will break downover time. The flexed body can be made of a material which will notcompletely break down until signal transmission is complete.

The conductor which connects the electrodes can be a flexible wire whichcan be embedded into the flexed body. In the cases where the flexed bodydissolves, the flexible conductive wire will remain, but will easilypass through the body due to its flexibility. Alternatively, a thinlayer of a conductor, such as gold, can be deposited on the surface ofthe flexed body to connect the electrodes. The conductor can also bemade of a material which will dissolve, such as edible gold foil. Thiswould leave the chip as the only indigestible portion of thetransmitter, which will pass through the body.

In some cases, it may be desirable for the transmitter not to deploy atthe same time the pill dissolves. One way to add a delay is to coat thetransmitter in with a material which does not dissolve in the sameenvironment as the pill material. For instance, cellulose acetatephthalate can be used as an enteric coating to coat the transmitter,causing it not to dissolve in the acidic environment of the stomach, butto dissolve in the small intestine. Because the onboard battery is notactivated until it becomes wet, the transmitter will not begin signaltransmission until the coating dissolves.

In some embodiments, multiple transmitters can be used in a single pill.This increases the likelihood that the pill will be detected by thereceiver. Also, if the transmitters are located at different depths inthe pill, or coated with different substances, this can give valuableinformation. For instance, if one transmitter is configured to begintransmission when it enters the stomach, and another is configured tobegin transmission when it enters the small intestine, this can give anindication of motility by tracking how long it takes for the pill totravel from the stomach to the small intestine.

FIG. 8A shows an embodiment of the mechanical multi-directionaltransmitter, with electrode and chip 128 connected to electrode 130 byflexed body 132. Electrode and chip 128 are electrically connected toelectrode 130 by a conductor, such as a wire, which is located in or onflexed body 132. Flexed body 132 is bent and twisted in a predeterminedform, and placed in pill 134 such that it is stuck in that form untilthe pill dissolves. For example, the transmitter can be embedded in theencapsulation layer of the pill to secure it.

FIG. 8B shows the orientation of transmit electrodes 128 and 130 in theconfiguration of FIG. 8A, placed in a Cartesian coordinate system forillustration purposes. In this configuration, the electrodes are alignedon the x-axis. A receiver with an antenna in parallel to the x-axiswould be in optimal orientation to receive the transmitted signal.

As the pill enters the desired location in the body, such as thestomach, it begins to dissolve. FIG. 8C shows the transmitter in anintermediate state. As the encapsulation layer 136 dissolves, the flexedbody 132 is no longer held in place, and begins to unfurl. As flexedbody 132 unravels, electrodes 128 and 130 move to a differentorientation relative to each other.

As shown in FIG. 8D, in the intermediate orientation, the electrodes arealigned along the y-axis. A receiver with an antenna in parallel to they-axis would be in optimal orientation to receive the transmittedsignal.

FIGS. 8E-F show the transmitter in its final orientation after the pillhas completely dissolved, and the flexed body 132 is allowed to returnto its natural orientation. In the final orientation, electrodes 128 and130 are aligned along the z-axis. A receiver with an antenna in parallelto the z-axis would be in optimal orientation to receive the transmittedsignal.

It should be noted that the signal sweeping process is continuous, andthe orientation of the electrodes will be continuously changing duringthe process. FIGS. 8C-D show just one of the intermediate orientationsof the transmit electrodes.

In a healthy stomach, the transmitter may naturally change orientationdue to contractions in the stomach, giving some degree ofmulti-directionality. In these cases, the multi-directional transmittercan serve to supplement the natural rotations. Also, in cases where thepill and/or transmitter is stuck on a wall, or in a less active portionof the stomach or digestive tract, the multi-directionality of thetransmitter is even more important. For instance, the pill and/ortransmitter can become stuck in the ruggae, or a less active region ofthe stomach such as the fundus. The sweeping motion of the transmittermay also serve to dislodge the pill and/or transmitter if it is stuck.Some patients suffer from low stomach activity, and may especiallybenefit from a pill with a multi-directional transmitter.

The multi-directional transmitter discussed above is not limited to usein conjunction with a pharmaceutical pill. The transmitter can bedisposed on a sensor or other unit which travels or is implanted in thebody, in order to wirelessly transmit data in multiple directions.

As reviewed above, the circuitry that drives the identifier may includea number of different functional blocks, e.g., signal generation blocks,activation blocks, transmitter blocks, a power source, etc. In certainembodiments, these functional blocks are provided in the form of anintegrated circuit, where the integrated circuits of these embodimentsinclude a number of distinct functional blocks, i.e., modules, where thefunctional blocks are all present in a single integrated circuit on anintraluminal-sized support. By single integrated circuit is meant asingle circuit structure that includes all of the different functionalblocks. As such, the integrated circuit is a monolithic integratedcircuit (also known as IC, microcircuit, microchip, silicon chip,computer chip or chip) that is a miniaturized electronic circuit (whichmay include semiconductor devices, as well as passive components) thathas been manufactured in the surface of a thin substrate ofsemiconductor material. The integrated circuits of certain embodimentsof the present invention are distinct from hybrid integrated circuits,which are miniaturized electronic circuits constructed of individualsemiconductor devices, as well as passive components, bonded to asubstrate or circuit board.

The support with which the circuit is associated, e.g., by being presenton surface of the support or integrated, at least partially, inside ofthe support, may be any convenient support, and may be rigid or flexibleas desired. As the support is intraluminal sized, its dimensions aresuch that it can be positioned inside of a physiological lumen, e.g.,inside of a vessel, such as a cardiac vessel, e.g., a vein or artery. Incertain embodiments, the intraluminal sized integrated circuits have asize (e.g., in terms of surface area of largest surface) of betweenabout 0.05 mm² and about 5 mm², such as between about 1.125 mm² andabout 2.5 mm², and including about 1.5 mm². The supports of theintegrated circuits can have a variety of different shapes, such assquare, rectangle, oval, and hexagon, irregular, etc.

The transmitter may include dedicated circuitry which is configured toprovide for the desired transmission protocol.

As reviewed above, the circuitry that drives the identifier may includea number of different functional blocks, e.g., signal generation blocks,activation blocks, transmitter blocks, etc. In certain embodiments,these functional blocks are provided in the form of an integratedcircuit, where the integrated circuits of these embodiments include anumber of distinct functional blocks, i.e., modules, where thefunctional blocks are all present in a single integrated circuit on anintraluminal-sized support. By single integrated circuit is meant asingle circuit structure that includes all of the different functionalblocks. As such, the integrated circuit is a monolithic integratedcircuit (also known as IC, microcircuit, microchip, silicon chip,computer chip or chip) that is a miniaturized electronic circuit (whichmay include semiconductor devices, as well as passive components) thathas been manufactured in the surface of a thin substrate ofsemiconductor material. The integrated circuits of certain embodimentsof the present invention are distinct from hybrid integrated circuits,which are miniaturized electronic circuits constructed of individualsemiconductor devices, as well as passive components, bonded to asubstrate or circuit board.

The support with which the circuit is associated, e.g., by being presenton surface of the support or integrated, at least partially, inside ofthe support, may be any convenient support, and may be rigid or flexibleas desired. As the support is intraluminal sized, its dimensions aresuch that it can be positioned inside of a physiological lumen, e.g.,inside of a vessel, such as a cardiac vessel, e.g., a vein or artery. Incertain embodiments, the intraluminal sized integrated circuits have asize (e.g., in terms of surface area of largest surface) of betweenabout 0.05 mm² and about 5 mm², such as between about 1.125 mm² andabout 2.5 mm², and including about 1.5 mm². The supports of theintegrated circuits can have a variety of different shapes, such assquare, rectangle, oval, and hexagon, irregular, etc.

Other configurations for the circuitry are of course possible. Otherconfigurations of interest include, but are not limited to, thosedescribed in PCT application serial no. PCT/US2006/016370 filed on Apr.28, 2006 and titled “Pharma-Informatics System”; PCT application serialno. PCT/US2007/022257 filed on Oct. 17, 2007 and titled “In-vivo LowVoltage Oscillator for Medical Devices”; PCT application serial no.PCT/US US2007/82563 filed on Oct. 25, 2007 and titled “ControlledActivation Ingestible Identifier”; U.S. patent application Ser. No.11/776,480 filed Jul. 11, 2007 entitled “Acoustic Pharma InformaticsSystem”; and PCT application serial no. PCT/US2008/52845 filed on Feb.1, 2008 and titled “Ingestible Event Marker Systems”; the disclosures ofwhich applications (and particularly signal generation componentsthereof) are herein incorporated by reference.

The identifiers may be fabricated using any convenient processingtechnology. In certain embodiments, planar processing protocols areemployed to fabricate power sources having surface electrodes, where thesurface electrodes include at least an anode and cathode at leastpartially on the same surface of a circuitry support element. In someembodiments, the power source can comprise a battery. In certainembodiments, planar processing protocols are employed in a wafer bondingprotocol to produce a battery source. Planar processing techniques, suchas Micro-Electro-Mechanical Systems (MEMS) fabrication techniques,including surface micromachining and bulk micromachining techniques, maybe employed. Deposition techniques that may be employed in certainembodiments of fabricating the structures include, but are not limitedto: electrodeposition (e.g., electroplating), cathodic arc deposition,plasma spray, sputtering, e-beam evaporation, physical vapor deposition,chemical vapor deposition, plasma enhanced chemical vapor deposition,etc. Material removal techniques included, but are not limited to:reactive ion etching, anisotropic chemical etching, isotropic chemicaletching, planarization, e.g., via chemical mechanical polishing, laserablation, electronic discharge machining (EDM), etc. Also of interestare lithographic protocols. Of interest in certain embodiments is theuse of planar processing protocols, in which structures are built upand/or removed from a surface or surfaces of an initially planarsubstrate using a variety of different material removal and depositionprotocols applied to the substrate in a sequential manner. Illustrativefabrication methods of interest are described in greater detail incopending PCT application serial no. PCT/US2006/016370; the disclosureof which is herein incorporated by reference.

Optional Physiologically Acceptable Carrier Component

Identifiers of the invention that include multi-directional transmittersas described above may be present in (i.e., combined with) aphysiologically acceptable carrier component, e.g., a composition orvehicle that aids in ingestion of the identifier and/or protects theidentifier until it reaches the target site of interest. Byphysiologically acceptable carrier component” is meant a composition,which may be a solid or fluid (e.g., liquid), which has is ingestible.

Common carriers and excipients, such as corn starch or gelatin, lactose,dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol,dicalcium phosphate, sodium chloride, and alginic acid are of interest.Disintegrators commonly used in the formulations of the inventioninclude croscarmellose, microcrystalline cellulose, corn starch, sodiumstarch glycolate and alginic acid.

A liquid composition may comprise a suspension or solution of thecompound or pharmaceutically acceptable salt in a suitable liquidcarrier(s), for example, ethanol, glycerine, sorbitol, non-aqueoussolvent such as polyethylene glycol, oils or water, with a suspendingagent, preservative, surfactant, wetting agent, flavoring or coloringagent. Alternatively, a liquid formulation can be prepared from areconstitutable powder. For example, a powder containing activecompound, suspending agent, sucrose and a sweetener can be reconstitutedwith water to form a suspension; and a syrup can be prepared from apowder containing active ingredient, sucrose and a sweetener.

A composition in the form of a tablet or pill can be prepared using anysuitable pharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample, polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

“Controlled release”, “sustained release”, and similar terms are used todenote a mode of active agent delivery that occurs when the active agentis released from the delivery vehicle at an ascertainable andcontrollable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the polyorthoester. Therate of hydrolysis in turn may be controlled by the composition of thepolyorthoester and the number of hydrolysable bonds in thepolyorthoester. Other factors determining the rate of release of anactive agent from the present pharmaceutical composition includeparticle size, acidity of the medium (either internal or external to thematrix) and physical and chemical properties of the active agent in thematrix.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, for example, by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example, liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.

Tablet binders that can be included are acacia, methylcellulose, sodiumcarboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch and ethylcellulose. Lubricants that canbe used include magnesium stearate or other metallic stearates, stearicacid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherryflavoring or the like can also be used. Additionally, it may bedesirable to add a coloring agent to make the dosage form moreattractive in appearance or to help identify the product.

Other components suitable for use in the formulations of the presentinvention can be found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985).

Optional Active Agent

In certain embodiments, the identifier is not associated with apharmaceutically active agent. As such, the identifier, and any carrieror other component that make up the ingestible event marker, do notinclude an active agent.

In yet other embodiments, the identifier is associated with an activeagent, e.g., where the active agent is present in the carriercomposition that includes the identifier. In some embodiments, thesignal generation element can be stably associated with an active agent.By “active agent/carrier component” is meant a composition, which may bea solid or fluid (e.g., liquid), which has an amount of active agent,e.g., a dosage, present in a pharmaceutically acceptable carrier. Theactive agent/carrier component may be referred to as a “dosageformulation.”

“Active agent” includes any compound or mixture of compounds whichproduces a physiological result, e.g., a beneficial or useful result,upon contact with a living organism, e.g., a mammal, such as a human.Active agents are distinguishable from such components as vehicles,carriers, diluents, lubricants, binders and other formulating aids, andencapsulating or otherwise protective components. The active agent maybe any molecule, as well as binding portion or fragment thereof, that iscapable of modulating a biological process in a living subject. Incertain embodiments, the active agent may be a substance used in thediagnosis, treatment, or prevention of a disease or as a component of amedication. In certain embodiments, the active agent may be a chemicalsubstance, such as a narcotic or hallucinogen, which affects the centralnervous system and causes changes in behavior.

The active agent (i.e., drug) is capable of interacting with a target ina living subject. The target may be a number of different types ofnaturally occurring structures, where targets of interest include bothintracellular and extracellular targets. Such targets may be proteins,phospholipids, nucleic acids and the like, where proteins are ofparticular interest. Specific proteinaceous targets of interest include,without limitation, enzymes, e.g., kinases, phosphatases, reductases,cyclooxygenases, proteases and the like, targets comprising domainsinvolved in protein-protein interactions, such as the SH2, SH3, PTB andPDZ domains, structural proteins, e.g., actin, tubulin, etc., membranereceptors, immunoglobulins, e.g., IgE, cell adhesion receptors, such asintegrins, etc., ion channels, transmembrane pumps, transcriptionfactors, signaling proteins, and the like.

The active agent (i.e., drug) may include one or more functional groupsnecessary for structural interaction with the target, e.g., groupsnecessary for hydrophobic, hydrophilic, electrostatic or even covalentinteractions, depending on the particular drug and its intended target.Where the target is a protein, the drug moiety may include functionalgroups necessary for structural interaction with proteins, such ashydrogen bonding, hydrophobic-hydrophobic interactions, electrostaticinteractions, etc., and may include at least an amine, amide,sulfhydryl, carbonyl, hydroxyl or carboxyl group, such as at least twoof the functional chemical groups.

Drugs of interest may include cyclical carbon or heterocyclic structuresand/or aromatic or polyaromatic structures substituted with one or moreof the above functional groups. Also of interest as drug moieties arestructures found among biomolecules, including peptides, saccharides,fatty acids, steroids, purines, pyrimidines, derivatives, structuralanalogs or combinations thereof. Such compounds may be screened toidentify those of interest, where a variety of different screeningprotocols are known in the art.

The active agent may be derived from a naturally occurring or syntheticcompound that may be obtained from a wide variety of sources, includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including the preparation ofrandomized oligonucleotides and oligopeptides. Alternatively, librariesof natural compounds in the form of bacterial, fungal, plant and animalextracts are available or readily produced. Additionally, natural orsynthetically produced libraries and compounds are readily modifiedthrough conventional chemical, physical and biochemical means, and maybe used to produce combinatorial libraries. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification, etc. to producestructural analogs.

As such, the active agent may be obtained from a library of naturallyoccurring or synthetic molecules, including a library of compoundsproduced through combinatorial means, i.e., a compound diversitycombinatorial library. When obtained from such libraries, the drugmoiety employed will have demonstrated some desirable activity in anappropriate screening assay for the activity. Combinatorial libraries,as well as methods for producing and screening such libraries, are knownin the art and described in: U.S. Pat. Nos. 5,741,713; 5,734,018;5,731,423; 5,721,099; 5,708,153; 5,698,673; 5,688,997; 5,688,696;5,684,711; 5,641,862; 5,639,603; 5,593,853; 5,574,656; 5,571,698;5,565,324; 5,549,974; 5,545,568; 5,541,061; 5,525,735; 5,463,564;5,440,016; 5,438,119; 5,223,409, the disclosures of which are hereinincorporated by reference.

Broad categories of active agents of interest include, but are notlimited to: cardiovascular agents; pain-relief agents, e.g., analgesics,anesthetics, anti-inflammatory agents, etc.; nerve-acting agents;chemotherapeutic (e.g., anti-neoplastic) agents; etc.

A variety of manufacturing protocols may be employed to producecompositions as described above, e.g., where an identifier is present inpharmaceutically acceptable carrier or vehicle, where the carrier orvehicle may further include one or more active agents. In manufacturingsuch compositions, an identifier is stably associated with thepharmaceutical dosage from in some manner. By stably associated is meantthat the identifier and the dosage form do not separate from each other,at least until administered to the subject in need thereof, e.g., byingestion. The identifier may be stably associated with thepharmaceutical carrier/active agent component of the composition in anumber of different ways. In certain embodiments, where thecarrier/active agent component is a solid structure, e.g., such as atablet or pill, the carrier/active agent component is produced in amanner that provides a cavity for the identifier. The identifier is thenplaced into the cavity and the cavity sealed, e.g., with a biocompatiblematerial, to produce the final composition. For example, in certainembodiments a tablet is produced with a die that includes a featurewhich produces a cavity in the resultant compressed tablet. Theidentifier is placed into the cavity and the cavity sealed to producethe final tablet. In a variation of this embodiment, the tablet iscompressed with a removable element, e.g., in the shape of a rod orother convenient shape. The removable element is then removed to producea cavity in the tablet. The identifier is placed into the cavity and thecavity sealed to produce the final tablet. In another variation of thisembodiment, a tablet without any cavity is first produced and then acavity is produced in the tablet, e.g., by laser drilling. Theidentifier is placed into the cavity and the cavity sealed to producethe final tablet. In yet other embodiments, a tablet is produced bycombining the identifier with subparts of the tablet, where the subpartsmay be pre-made subparts or manufactured sequentially. For example, incertain embodiments tablets are produced by first making a bottom halfof the tablet, placing the signal generation element on a location ofthe bottom half of the tablet, and then placing top portion of thetablet over the bottom half and signal generation element to produce thefinal desired composition. In certain embodiments, a tablet is producedaround an identifier such that the identifier is located inside of theproduced tablet. For example, an identifier, which may or may not beencapsulated in a biocompatible compliant material, e.g., gelatin (toprotect the signal generation element), is combined with carrier/activeagent precursor, e.g., powder, and compressed or molded into a tablet ina manner such that the identifier is located at an internal position ofthe tablet. Instead of molding or compressing, the carrier/active agentcomponent is, in certain embodiments, sprayed onto an identifier in amanner that builds up the tablet structure. In yet another embodiment,the active agent/carrier component precursor may be a liquid formulationwhich is combined with the identifier and then solidified to produce thefinal composition. In yet other embodiments, pre-made tablets may befitted with an identifier by stably attaching an identifier to thetablet. Of interest are protocols that do not alter the properties ofthe tablet, e.g., dissolution etc. For example, a gelatin element thatsnap fits onto one end of a tablet and has an identifier integrated withit is employed in certain embodiments. The gelatin element is colored incertain embodiments to readily identify tablets that have been fittedwith the signal generation element. Where the composition has an activeagent/carrier composition filled capsule configuration, e.g., such as agelatin capsule filled configuration, an identifier may be integratedwith a capsule component, e.g., top or bottom capsule, and the capsulefilled with the active agent/carrier composition to produce the finalcomposition. The above reviewed methods of manufacture are merelyillustrative of the variety of different ways in which the compositionsof the invention may be manufactured.

In certain embodiments, the identifiers are disrupted uponadministration to a subject. As such, in certain embodiments, thecompositions are physically broken, e.g., dissolved, degraded, eroded,etc., following delivery to a body, e.g., via ingestion, injection, etc.The compositions of these embodiments are distinguished from devicesthat are configured to be ingested and survive transit through thegastrointestinal tract substantially, if not completely, intact.

Systems

Also provided are systems that include the subject compositions. Systemsof the subject invention include, in certain embodiments, an ingestibleor implantable event marker comprising one or more devices that includea deployable antenna of the invention, e.g., an identifier as reviewedabove, as well as a signal detection component, e.g., in the form of areceiver. The signal detection component may vary significantlydepending on the nature of the signal that is generated by the signalgeneration element of the composition, e.g., as reviewed above.

Signal receivers of systems of embodiments of the invention are thosethat are configured to receive a signal from an identifier, e.g., toreceive a signal emitted by an identifier upon contact of the identifierwith the target physiological site following ingestion of theidentifier. The signal receiver may vary significantly depending on thenature of the signal that is generated by the signal generation element,e.g., as reviewed below. As such, the signal receiver may be configuredto receive a variety of different types of signals, including but notlimited to: RF signals, magnetic signals, conductive (near field)signals, acoustic signals, etc., as indicated above. In certainembodiments, the receiver is configured to receive a signal conductivelyfrom another component, e.g. the identifier, such that the twocomponents use the body of the patient as a communication medium. Assuch, the signal that is transferred between identifier and the receivertravels through the body, and requires the body as the conductionmedium. The identifier emitted signal may be transmitted through andreceived from the skin and other body tissues of the subject body in theform of electrical alternating current (a.c.) voltage signals that areconducted through the body tissues. As a result, such embodiments do notrequire any additional cable or hard wire connection, or even a radiolink connection for transmitting the sensor data from the autonomoussensor units to the central transmitting and receiving unit and othercomponents of the system, since the sensor data are directly exchangedvia the skin and other body tissues of the subject. This communicationprotocol has the advantage that the receivers may be adaptably arrangedat any desired location on the body of the subject, whereby thereceivers are automatically connected to the required electricalconductor for achieving the signal transmission, i.e., the signaltransmission is carried out through the electrical conductor provided bythe skin and other body tissues of the subject. In certain embodiments,the signal detection component is one that is activated upon detectionof a signal emitted from an identifier. In certain embodiments, thesignal receiver is capable of (i.e., configured to) simultaneouslydetecting multiple different signals, e.g., 2 or more, 5 or more, 10 ormore, etc.

The signal receiver may include a variety of different types of signalreceiver elements, where the nature of the receiver element necessarilyvaries depending on the nature of the signal produced by the signalgeneration element. In certain embodiments, the signal receiver mayinclude one or more electrodes (e.g., 2 or more electrodes, 3 or moreelectrodes, and/or includes multiple, e.g., 2 or more, 3 or more, 4 ormore pairs of electrodes, etc.) for detecting signal emitted by thesignal generation element. In certain embodiments, the receiver devicewill be provided with two electrodes that are dispersed at a distance,e.g., a distance that allows the electrodes to detect a differentialvoltage. This distance may vary, and in certain embodiments ranges fromabout 0.1 to about 5 cm, such as from about 0.5 to about 2.5 cm, e.g.,about 1 cm. In an alternative embodiment, a receiver that utilizes asingle electrode is employed. In certain embodiments, the signaldetection component may include one or more coils for detecting signalemitted by the signal generation element. In certain embodiments, thesignal detection component includes an acoustic detection element fordetecting signal emitted by the signal generation element. In certainembodiments, multiple pairs of electrodes (e.g., as reviewed above) areprovided, for example to increase detection probability of the signal.

The signal receivers of interest include both external and implantablesignal receivers. In external embodiments, the signal receiver is exvivo, by which is meant that the receiver is present outside of the bodyduring use. Where the receiver is implanted, the signal receiver is invivo. The signal receiver is configured to be stably associated with thebody, e.g., either in vivo or ex vivo, at least during the time that itreceives the emitted signal from the IEM.

Signal receivers of interest include, but are not limited to, thosereceivers disclosed in: PCT application serial no. PCT/US2006/016370filed on Apr. 28, 2006 and titled “Pharma-Informatics System”; and PCTapplication serial no. PCT/US2008/52845 filed on Feb. 1, 2008 and titled“Ingestible Event Marker Systems”; the disclosures of which applications(and particularly signal receiver components thereof) are hereinincorporated by reference.

In certain embodiments, the signal receiver is configured to providedata of a received signal to a location external to said subject. Forexample, the signal receiver may be configured to provide data to anexternal data receiver, e.g., which may be in the form of a monitor(such as a bedside monitor), a computer (e.g., PC or MAC), a personaldigital assistant (PDA), phone, messaging device, smart phone, etc. Inone embodiment, if a signal receiver failed to detect a signalindicating that a pill had been ingested, the signal receiver couldtransmit a reminder to take the pill to the subject's PDA or smartphone, which could then provide a prompt to the user to take themedication, e.g., a display or alarm on the PDA, by receiving a phonecall on the smart phone (e.g., a recorded message) etc. The signalreceiver may be configured to retransmit data of a received signal tothe location external to said subject. Alternatively, the signalreceiver according may be configured to be interrogated by an externalinterrogation device to provide data of a received signal to an externallocation.

As such, in certain embodiments the systems include an external devicewhich is distinct from the receiver (which may be implanted or topicallyapplied in certain embodiments), where this external device provides anumber of functionalities. Such an apparatus can include the capacity toprovide feedback and appropriate clinical regulation to the patient.Such a device can take any of a number of forms. By example, the devicecan be configured to sit on the bed next to the patient, e.g., a bedsidemonitor. Other formats include, but are not limited to, PDAs, smartphones, home computers, etc. The device can read out the informationdescribed in more detail in other sections of the subject patentapplication, both from pharmaceutical ingestion reporting and fromphysiological sensing devices, such as is produced internally by apacemaker device or a dedicated implant for detection of the pill. Thepurpose of the external apparatus is to get the data out of the patientand into an external device. One feature of the external apparatus isits ability to provide pharmacologic and physiologic information in aform that can be transmitted through a transmission medium, such as atelephone line, to a remote location such as a clinician or to a centralmonitoring agency.

Methods

Aspects of the invention further include methods of using in-bodydevices that include transmitters of the invention. Generally, methodsof the invention will include placing the in-body device in some mannerin the body of the subject, e.g., by implanting the device in a subject,by ingesting the device, etc. The devices may be employed with a varietyof subjects. Generally such subjects are “mammals” or “mammalian,” wherethese terms are used broadly to describe organisms which are within theclass mammalia, including the orders carnivore (e.g., dogs and cats),rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g.,humans, chimpanzees, and monkeys). In certain embodiments, the subjectswill be humans. Following placement of the devices in the body of asubject, the devices are employed for a variety of purposes, e.g., tosense one or more physiological parameters, to deliver one or moretherapies, to mark a personal event of interest, etc.

In certain embodiments, the in-body devices are ingestible devices,where the transmitter is part of an identifier of the device. In suchembodiments, the identifier is ingested and a signal emitted by theidentifier is detected, e.g., with a receiver as described above. Suchmethods are further described in PCT application serial no.PCT/US2006/016370 filed on Apr. 28, 2006 and titled “Pharma-InformaticsSystem”; and PCT application serial no. PCT/US US2008/52845 filed onFeb. 1, 2008 and titled “Ingestible Event Marker Systems”; thedisclosures of which applications (and particularly signal receivercomponents thereof) are herein incorporated by reference.

Utility

Devices that include the multi-directional transmitters of the inventionmay be employed in a variety of different applications, including boththerapeutic and non-therapeutic applications. Specific applications ofinterest include, but are not limited to: those applications describedin PCT application serial no. PCT/US2006/016370 filed on Apr. 28, 2006and titled “Pharma-Informatics System”; and PCT application serial no.PCT/US US2008/52845 filed on Feb. 1, 2008 and titled “Ingestible EventMarker Systems”; the disclosures of which applications (and particularlysignal receiver components thereof) are herein incorporated byreference.

IEM in body devices of the invention may be employed in a variety ofdifferent applications, which applications may be both medical andnon-medical in nature. Different illustrative applications are nowreviewed in greater detail below.

Certain applications involve the use of IEMs by themselves to mark apersonal event of interest, e.g., onset of a physiological parameter(such as a symptom(s) of interest), onset of an activity, etc. Forexample, in certain embodiments, event markers are employed to mark theonset of a symptom of interest. In such instances, when an individualbecomes aware of a symptom of interest, e.g., begins to feel flushed,nauseous, excited, etc., e.g., the individual may ingest an IEM to markthe occurrence of the symptom of interest. For example, the patient maybegin to not feel well, and ingest an event marker in response to thisill feeling. Upon ingestion, the marker sends a signal to a receiver,which may then record receipt of the signal for further use, e.g., tocombine with physiological data, etc. In certain embodiments, thereceived signal is employed to provide context for any physiologicaldata that is obtained from the patient, e.g., by sensors on thereceiver, from an implantable recorder, etc.

Another symptom of interest is pain. In these embodiments, theingestible event marker may be employed as a pain marker. For example,in the case where a patient is being monitored for pain, if a patientfeels no pain, the patient may ingest a first type of marker. If thepatient feels pain, the patient may ingest a second type of marker.Different types of markers may be differentiated, such as color coded,where desired, to assist in their identification and proper use by thepatient. For example, markers to be ingested when the patient does notfeel pain may be color coded blue, while markers that are to be ingestedwhen the patient does have pain may be color coded yellow. In anotherembodiment, instead of having different types of markers, a protocol maybe employed in which the number of markers ingested, and therefore thesignal obtained, e.g., from a single marker or two or more markers, isemployed to denote a scale of the symptom of interest, such as pain. Forexample, if an individual is having intense pain, the individual takesfour of the positive pain marker pills at the same time, while inresponse to mild pain the individual may take only one marker.

In such embodiments, the onset of the symptom of interest, as marked bythe ingestion of the event marker and detection of the signal by thereceiver, may be employed as relevant point at which to begin recordingone or more physiological parameters of interest, e.g., by using animplantable physiological monitor. In these instances, the emittedsignal from the marker is received by the receiver, which then causes aphysiological parameter recorder (such as a Reveal® Plus Insertable LoopRecorder (ILR), Medtronic Corporation) to begin recording data andsaving the data, e.g., for later use. For example, an implantablephysiological parameter recorder may have only a limited possible amountof time for recording (such as 42 minutes). In such situations, the datamay be automatically overwritten unless somehow flagged or marked forprotection. In the present methods, an IEM may be ingested to mark theonset of a symptom of interest, as perceived by the patient, and thereceiver upon receipt of the signal may act with the recorder to protectthe data obtained around the time of the signal (after, or even sometime before) to be protected and not overwritten. The system may befurther configured to work in response not only to the ingestion of theevent marker, but also in response to physiological sensed parameters,e.g., pH. As such, the methods find use as an event recorder in terms offlagging a diagnostic stream of information, and protecting it frombeing overwritten, so a physician can look at it at a later date.

In certain embodiments, the event marker provides the context forinterpreting a given set of physiological data at a later time. Forexample, if one is employing an activity sensor and one co-administersan event marker with a particular drug, one can note any change inactivity that is brought about by that drug. If a drop in activity isobserved after a person takes both the event marker and a drug, the dropindicates the drug is probably causing the person to reduce theiractivity, e.g., by making them feel sleepy or actually causing them tofall asleep. Such data may be employed to adjust the dose of a drug orbe the basis for a decision to switch to an alternative medication.

In certain embodiments the event marker is employed to construct adatabase of multiple events. Such a database may be employed to findcommonality between the multiple marked events. Simple or complexprotocols for finding commonality among multiple marked events may beemployed. For example, multiple events may be averaged. Alternativelytechniques such as impulse response theory may be employed, where suchtechniques provide information on what exactly are the common featuresin a set of multiple sensor streams that are tied to a particular event.

The IEM systems of the invention enable one to use subjective symptoms,such as “I'm feeling funny,” to impart context and background toobtained objective measures of what is occurring physiologically. Forexample, if every time a subject felt abnormal they took an eventmarker, one could reference a database of the objective sensor data, andfind common features in the database. Such an approach may be employedto discover the underlying causes of the subjective feeling. Forexample, such an approach may be employed to determine that every time apatient is feeling “funny”, there is an associated change in their bloodpressure, and the link between a subjective symptom and objectivephysiological data can be used in their diagnosis. As such, ageneralizable event marker brings context to discrete data from anyother source. Therefore, use of the oral medication event markers canprovide context for any other associated health monitoring informationor health event.

In certain embodiments, the event marker can be an alert marker, suchthat ingestion of the marker causes an alarm signal to be sent from thepatient, e.g., indicating that the patient needs medical assistance. Forexample, when a patient feels an onset of a symptom of interest, such aschest pain, shortness of breath, etc., the patient may ingest an eventmarker. The signal emitted from the event marker may be received by thereceiver, which may then cause an alarm to be generated and distributedto a medical professional.

In certain embodiments, the event marker is employed to instigate orstart a therapeutic action, e.g., activate an implantable pulsegenerator to deliver electrical therapy, activate an implanted drugdelivery device to administer a dosage of drug, activate a physiologicalsensor to begin acquiring data, etc. For example, where a patient has aneural stimulator for treating migraines, upon perception of the onsetof aura, the patient could ingest an IEM. The emitted signal would thenactivate neural stimulator into stimulus mode, and thereby cause theimplant to deliver therapy. Alternatively, if one has an implanted drugdeliver device, e.g., a device that delivers an oncotic agent, ingestionof the IEM could cause the implanted device to deliver the active agent.

In certain embodiments, the event marker is employed to deliverinformation to an implanted medical device in the patient. For example,an ingestible event marker may send a signal that includes update datafor an implanted medical device, such as firmware upgrade data for animplantable pulse generator, e.g., a pace maker. In such instances, thesignal may include the upgrade code which is broadcast from the IEMconductively to the medical device, where upon receipt of the signal andcode, the firmware of the medical device is upgraded.

Other applications where event markers may be employed by themselves isto mark or note the start of non-medical personal event, such as acommute time, the start of an exercise regimen, sleep time, smoking(e.g., so one can log how much one smokes) etc.

As indicated above, embodiments of the invention are characterized inthat the event markers are co-ingested with another composition ofmatter, e.g., a pharmaceutical composition, food, etc, where the eventmarker may or may not be present in the same composition as theco-ingested matter. For example, the event markers may be employed totrack ingesting a pharmaceutical agent, where one co-administers themarker with the drug of interest. Applications where co-administrationof a drug and marker is of interest include, but are not limited to,clinical studies, titration of medicine, e.g., blood pressure medicine,etc. Where desired, the IEM could be provided as just another pill toindicate when a refill is needed from the pharmacy.

Instead of co-ingesting the event marker with another composition, e.g.,a drug, food, etc., the marker and the other composition may becompounded together, e.g., by the end user. For example, an IEM in theform of a capsule can be opened by the end user and filled with apharmaceutical composition. The resultant compounded capsule and activeagent may then be ingested by the end user. Instead of an end user, thepharmacist or a health care provider may perform the compounding step.

In yet other embodiments, the marker is present already compounded withthe other composition at the source of manufacture of the othercomposition, e.g., the manufacturer or producer of a pharmaceuticalcomposition. An example of such compositions includes those described inPCT application serial no. PCT/US2006/016370; the disclosure of which isherein incorporated by reference.

In certain embodiments, the IEMs of the invention are employed to allowone to look at, on an individual basis, what a given result is withrespect to what drugs an individual is taking versus their impact onindicators that correlate to the desired effect. For example, where agiven patient is prescribed a regimen of multiple pharmaceutical agentsand there are multiple different physiological parameters that aremonitored as indicators of how the patient is responding to theprescribed therapeutic regimen, a given drug as marked by a given markercan be assessed in terms of its impact on one or more of thephysiological parameters of interest. Following this assessment,adjustments can be made accordingly. In this manner, automation may beemployed to tailor therapies based on individual responses. For example,where a patient is undergoing oncotic therapy, the event marker can beused to provide real time context to obtained physiological parameterdata. The resultant annotated real time data can be used to makedecisions about whether or not to continue therapy, or change to a newtherapy.

In certain embodiments, a dosing event (as marked by the IEM) iscorrelated with sensor data to develop a profile for how a given drugacts, e.g., in terms of a pharmacokinetic and/or pharmacodynamic model.Sensors are employed with the IEM marking of the dosing event to obtaina pharmacokinetic model. Once a pharmacokinetic model is derived, onecan use the dosing event to drive that model and predict serum druglevels and response. One might find, as determined from various sensors,that a patient is not responding well to therapy at a particular time.One might look back at the pharmacokinetic model to find that the levelsof the therapeutic drug in the blood are low when the patient is notresponding well, based on symptoms and/or objective physiological data.This data can then be used to make a determination to increase thedosing frequency or increase the dose level at a given dosing event. Theevent marker can therefore provide provides a way to develop apharmacokinetic and/or pharmacodynamic model and then apply it tooptimize patient therapy.

Where the IEMs are co-administered with a pharmaceutical agent, e.g., astwo separate compositions or a single composition (as described above),the systems of the invention, enable a dynamic feedback and treatmentloop of tracking medication timing and levels, measuring the response totherapy, and recommending altered dosing based on the physiology andmolecular profiles of individual patients. For example, a symptomaticheart failure patient takes multiple drugs daily, primarily with thegoal of reducing the heart's workload and improving patient quality oflife. Mainstays of therapy include angiotensin converting enzyme (ACE)inhibitors, β-blockers and diuretics. For pharmaceutical therapy to beeffective, it is vital that patients adhere to their prescribed regimen,taking the required dose at the appropriate time. Multiple studies inthe clinical literature demonstrate that more than 50% of Class II andIII heart failure patients are not receiving guideline-recommendedtherapy, and, of those who are titrated appropriately, only 40-60%adhere to the regimen. With the subject systems, heart failure patientscan be monitored for patient adherence to therapy, and adherenceperformance can be linked to key physiologic measurements, to facilitatethe optimization of therapy by physicians.

In certain embodiments, the systems of the invention may be employed toobtain an aggregate of information that includes sensor data andadministration data. For example, one can combine the heart rate, therespiration rate, multi-axis acceleration data, something about thefluid status, and something about temperature, and derive indices thatwill inform about the total activity of the subject, that can be used togenerate a physiological index, such as an activity index. For instance,when there is a rise in temperature, heart rate goes up a bit, andrespiration speeds up, which may be employed as an indication that theperson is being active. By calibrating this, the amount of calories theperson is burning at that instant could be determined. In anotherexample, a particular rhythmic set of pulses or multi-axis accelerationdata can indicate that a person is walking up a set of stairs, and fromthat one can infer how much energy they are using. In anotherembodiment, body fat measurement (e.g. from impedance data) could becombined with an activity index generated from a combination of measuredbiomarkers to generate a physiological index useful for management of aweight loss or cardiovascular health program. This information can becombined with cardiac performance indicators to get a good picture ofoverall health, which can be combined with pharmaceutical therapyadministration data. In another embodiment, one might find for examplethat a particular pharmaceutical correlates with a small increase inbody temperature, or a change in the electrocardiogram. One can developa pharmacodynamic model for the metabolism of the drug, and use theinformation from the receiver to essentially fit the free parameters inthat model to give much more accurate estimation of the levels actuallypresent in the serum of the subject. This information could be fed backto dosing regimes. In another embodiment, one can combine informationfrom a sensor that measures uterine contractions (e.g. with a straingauge) and that also monitors fetal heart rate, for use as a high-riskpregnancy monitor.

In certain embodiments, the subject specific information that iscollected using the systems of the invention may be transmitted to alocation where it is combined with data from one or more additionalindividuals to provide a collection of data which is a composite of datacollected from 2 or more, e.g., 5 or more, 10 or more, 25 or more, 50 ormore, 100 or more, 1000 or more, etc., individuals. The composite datacan then be manipulated, e.g., categorized according to differentcriteria, and made available to one or more different types of groups,e.g., patient groups, health care practitioner groups, etc., where themanipulation of data may be such as to limit the access of any givengroup to the type of data that group can access. For example, data canbe collected from 100 different individuals that are suffering from thesame condition and taking the same medication. The data can be processedand employed to develop easy to follow displays regarding patientcompliance with a pharmaceutical dosage regimen and general health.Patient members of the group can access this information and see howtheir compliance matches with other patient members of the group, andwhether they are enjoying the benefits that others are experiencing. Inyet another embodiment, doctors can also be granted access to amanipulation of the composite data to see how their patients arematching up with patients of other doctors, and obtain usefulinformation on how real patients respond to a given therapeutictreatment regiment. Additional functionalities can be provided to thegroups given access to the composite data, where such functionalitiesmay include, but are not limited to: ability to annotate data, chatfunctionalities, security privileges, etc.

The inventive pharmacokinetic model allows for drug dosing regimens tobe adjusted in real time in response to varying serum levels in thebody. The pharmacokinetic model can predict or measure the serum levelof a given medication in the body. This data can then be used tocalculate when the next dose of medication should be taken by thepatient. An alarm can be triggered at that time to alert the patient totake a dose. If the serum level remains high, an alarm can be triggeredto alert the patient not to take the next dose at the originallyprescribed time interval. The pharmacokinetic model can be used inconjunction with a medication ingestion monitoring system that includesan IEM, such as that described above. Data from this system can beincorporated into the model, as well as population data, measured data,and data input by the patient. Utilizing data from multiple sources, avery powerful and accurate tool can be developed.

In some embodiments, the data gathered by the receiver can be useddirectly by the pharmacokinetic model to determine when a medication wasadministered, what medication it was and in what amount. Thisinformation can be used to calculate an estimate of the serum level ofthe medication in the patient. Based on the calculated serum level, thepharmacokinetic model can send an alert to the patient to say eitherthat the serum level is too high and is near or above the toxic level,or that the serum level is too low and they should take another dose.The pharmacokinetic model can be run on the implanted receiver itself oron an external system which receives data from the implanted receiver.

A simple form of the pharmacokinetic model can assume that every patientis the same, and use average population data to model the serum level. Amore complex and more accurate model can be obtained by inputting otherinformation about the patient. This information can be inputted by theuser, such as a physician, or gathered by the receiver from associatedsensors. Information that can be used to adjust the model include othermedications being taken, diseases the patient suffers from, patient'sorgan function, enzyme levels, metabolism, body weight, and age, amongother factors. Information can also be inputted by the patientthemselves, such as if they feel hypoglycemic, or have pain ordizziness. This can be used as further evidence to validate thepredictions of the model.

Examples of food applications include the following. In certain diseaseconditions, such as diabetes, it can be important what a patient ate andwhen. In such instances, event markers of the invention are keyed orlinked to the type of food a patient eats. For example, one can have aset of event markers for different food items, and one can co-administerthem with the food items. From the resultant data, one can do a completeindividual metabolic profile on an individual. One knows how manycalories the patient is consuming. By obtaining activity and heart rateand ambient temperature versus body temperature data, one can calculatehow many calories one is expending. As a result, guidance can beprovided to the patient as to what foods to eat and when. Non diseasepatients may also track food ingestion in this manner. For example,athletes adhering to a strict training diet may employ IEMs to bettermonitor food ingestion and the effect of the food ingestion on one ormore physiological parameters of interest.

As reviewed in the above discussion, IEM systems of the invention finduse in both therapeutic and non-therapeutic applications. In therapeuticapplications, the IEM may or may not be compounded with apharmaceutically active agent. In those embodiments where the IEM iscompounded with active agent, the resultant compounded composition maybe viewed as a pharma-informatics enabled pharmaceutical composition.

In such pharma-informatics embodiments, an effective amount of acomposition that includes an IEM and an active agent is administered toa subject in need of the active agent present in the composition, where“effective amount” means a dosage sufficient to produce the desiredresult, e.g. an improvement in a disease condition or the symptomsassociated therewith, the accomplishment of a desired physiologicalchange, etc. The amount that is administered may also be viewed as atherapeutically effective amount. A “therapeutically effective amount”means the amount that, when administered to a subject for treating adisease, is sufficient to effect treatment for that disease.

The composition may be administered to the subject using any convenientmeans capable of producing the desired result, where the administrationroute depends, at least in part, on the particular format of thecomposition, e.g., as reviewed above. As reviewed above, thecompositions can be formatted into a variety of formulations fortherapeutic administration, including but not limited to solid, semisolid or liquid, such as tablets, capsules, powders, granules,ointments, solutions, suppositories and injections. As such,administration of the compositions can be achieved in various ways,including, but not limited to: oral, buccal, rectal, parenteral,intraperitoneal, intradermal, transdermal, intracheal, etc.,administration. In pharmaceutical dosage forms, a given composition maybe administered alone or in combination with other pharmaceuticallyactive compounds, e.g., which may also be compositions having signalgeneration elements stably associated therewith. In some embodiments,the signal generation element is stably associated with one or moreactive agents.

The subject methods find use in the treatment of a variety of differentconditions, including disease conditions. The specific diseaseconditions treatable by with the subject compositions are as varied asthe types of active agents that can be present in the subjectcompositions. Thus, disease conditions include, but are not limited to:cardiovascular diseases, cellular proliferative diseases, such asneoplastic diseases, autoimmune diseases, hormonal abnormality diseases,infectious diseases, pain management, and the like.

By treatment is meant at least an amelioration of the symptomsassociated with the disease condition afflicting the subject, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g. symptom, associated with thepathological condition being treated. As such, treatment also includessituations where the pathological condition, or at least symptomsassociated therewith, are completely inhibited, e.g. prevented fromhappening, or stopped, e.g. terminated, such that the subject no longersuffers from the pathological condition, or at least the symptoms thatcharacterize the pathological condition. Accordingly, “treating” or“treatment” of a disease includes preventing the disease from occurringin an animal that may be predisposed to the disease but does not yetexperience or exhibit symptoms of the disease (prophylactic treatment),inhibiting the disease (slowing or arresting its development), providingrelief from the symptoms or side-effects of the disease (includingpalliative treatment), and relieving the disease (causing regression ofthe disease). For the purposes of this invention, a “disease” includespain.

In certain embodiments, the subject methods, as described above, aremethods of managing a disease condition, e.g., over an extended periodof time, such as 1 week or longer, 1 month or longer, 6 months orlonger, 1 year or longer, 2 years or longer, 5 years or longer, etc. Thesubject methods may be employed in conjunction with one or moreadditional disease management protocols, e.g., electrostimulation basedprotocols in cardiovascular disease management, such as pacingprotocols, cardiac resynchronization protocols, etc; lifestyle, such adiet and/or exercise regimens for a variety of different diseaseconditions; etc.

In certain embodiments, the methods include modulating a therapeuticregimen based data obtained from the compositions. For example, data maybe obtained which includes information about patient compliance with aprescribed therapeutic regimen. This data, with or without additionalphysiological data, e.g., obtained using one or more sensors, such asthe sensor devices described above, may be employed, e.g., withappropriate decision tools as desired, to make determinations of whethera given treatment regimen should be maintained or modified in some way,e.g., by modification of a medication regimen and/or implant activityregimen. As such, methods of invention include methods in which atherapeutic regimen is modified based on signals obtained from thecomposition(s).

In certain embodiments, also provided are methods of determining thehistory of a composition of the invention, where the compositionincludes an active agent, an identifier element and a pharmaceuticallyacceptable carrier. In certain embodiments where the identifier emits asignal in response to an interrogation, the identifier is interrogated,e.g., by a wand or other suitable interrogation device, to obtain asignal. The obtained signal is then employed to determine historicalinformation about the composition, e.g., source, chain of custody, etc.

In certain embodiments, a system is employed that is made up of amultiple different IEMs, e.g., 2 or more distinct IEMS, 3 or moredistinct IEMS, 4 or more distinct IEMs, etc., including 5 or more, 7 ormore, 10 or more distinct IEMs. The distinct IEMs may be configured toprovide distinguishable signals, e.g., where the signals may bedistinguishable in terms of nature of the signal itself, in terms oftiming of emission of the signal, etc. For example, each IEM in suchsets may emit a differently coded signal. Alternatively, each IEM may beconfigured to emit the signal at a different physiological target site,e.g., where each IEM is configured to be activated at a different targetphysiological site, e.g., where an first IEM is activated in the mouth,a second is activated in the esophagus, a third is activated in thesmall intestine and a fourth is activated in the large intestine. Suchsets of multiple different distinguishable IEMs find use in a variety ofdifferent applications. For example, where one has the above described 4IEM set, one can use the set in a diagnostic application to determinefunction of the digestive system, e.g., motility through the digestivetract, gastric emptying etc. For example, by noting when each IEM emitsits respective signal, a plot of signal time may be generated from whichinformation regarding digestive tract functioning may be obtained.

The present invention provides the clinician an important new tool intheir therapeutic armamentarium: automatic detection and identificationof pharmaceutical agents actually delivered into the body. Theapplications of this new information device and system are multi-fold.Applications include, but are not limited to: (1) monitoring patientcompliance with prescribed therapeutic regimens; (2) tailoringtherapeutic regimens based on patient compliance; (3) monitoring patientcompliance in clinical trials; (4) monitoring usage of controlledsubstances; and the like. Each of these different illustrativeapplications is reviewed in greater detail below in copending PCTApplication Serial No. PCT/US2006/016370; the disclosure of which isherein incorporated by reference.

Additional applications in which the subject systems find use includethose described in U.S. Pat. No. 6,804,558, the disclosure of which isherein incorporated by reference. For example, the subject systems maybe used in a medical information communication system which permitsmonitoring the performance of an implantable medical device (IMD)implanted within a body of a patient, monitoring the health of thepatient, and/or remotely delivering a therapy to the patient through theIMD. A signal receiver of the invention, e.g., in an external formatsuch as a bandaid or implanted format, communicates with the IMD and iscapable of bidirectional communication with a communication module, amobile telephone and/or a Personal Data Assistant (PDA) located outsidethe patient's body. The system may comprise the IMD, the signal receiverwith the communication module and/or a mobile telephone and/or a PDA, aremote computer system, and a communication system capable ofbidirectional communication, where the communication module, the mobiletelephone and/or the PDA are capable of receiving information from theIMD or relaying information thereto via the signal receiver, which isinternal or external to the patient, as reviewed above.

Additional applications in which receivers of the invention may find useinclude, but are not limited to: fertility monitoring, body fatmonitoring, satiety monitoring, satiety control, total blood volumemonitoring, cholesterol monitoring, smoking detection, etc.

Kits

Also provided are kits that include one or more in-body devices of theinvention. Kits may include one or more in-body devices, e.g., asdescribed above, including ingestible and/or implantable event markers.In those embodiments having a plurality of in-body devices (e.g.ingestible event markers), such may be packaged in a single container,e.g., a single tube, bottle, vial, and the like, or one or more dosageamounts may be individually packaged such that certain kits may havemore than one container of an in-body device. In certain embodiments thekits may also include a signal receiving element, or receiver, asreviewed above. In certain embodiments, the kits may also include anexternal monitor device, e.g., as described above, which may provide forcommunication with a remote location, e.g., a doctor's office, a centralfacility etc., which obtains and processes data obtained about the usageof the composition.

The subject kits may also include instructions for how to practice thesubject methods using the components of the kit. The instructions may berecorded on a suitable recording medium or substrate. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or sub-packaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, etc. In yet other embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g. via the internet, are provided. An example ofthis embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Some or all components of the subject kits may be packaged in suitablepackaging to maintain sterility. In many embodiments of the subjectkits, the components of the kit are packaged in a kit containmentelement to make a single, easily handled unit, where the kit containmentelement, e.g., box or analogous structure, may or may not be an airtightcontainer, e.g., to further preserve the sterility of some or all of thecomponents of the kit.

It is to be understood that this invention is not limited to particularembodiments described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

Certain ranges have been presented herein with numerical values beingpreceded by the term “about.” The term “about” is used herein to provideliteral support for the exact number that it precedes, as well as anumber that is near to or approximately the number that the termprecedes. In determining whether a number is near to or approximately aspecifically recited number, the near or approximating unrecited numbermay be a number which, in the context in which it is presented, providesthe substantial equivalent of the specifically recited number.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. An apparatus for identification of an eventoccurring within a liquid environment, the apparatus comprising: asealed support structure; a control unit secured within the structurefor producing an identifiable electrical pattern upon contact of theapparatus with the liquid environment; and a plurality of transmissionelectrodes each capable of emanating the pattern, wherein the pluralityof transmission electrodes are distributed about the structure toconductively communicate with the liquid environment when the apparatusis in contact with the liquid environment, and wherein each transmissionelectrode is electrically coupled to the control unit, and wherein thecontrol unit comprises: a pattern control module; a multi-directionaltransmitter comprising the plurality of transmission electrodes andincluding a plurality of outputs, wherein each output is coupled to oneof the plurality of transmission electrodes, and wherein themulti-directional transmitter is configured to operate as at least oneof a monopole transmitter or a dipole transmitter; and wherein thecontrol unit controls electrical current conducted through the liquidenvironment from the plurality of transmission electrodes to emanate thepattern using at least two directions, and wherein emanation of thepattern corresponds to contact between the apparatus and the liquid;wherein the plurality of transmission electrodes comprise a first,second and third emanating elements and the control unit is configuredto produce the pattern using the following sequence of emanatingelements: the first and second emanating elements; the second and thirdemanating elements; and the third and first emanating elements.
 2. Theapparatus of claim 1, wherein the multi-directional transmitter isconfigured to operate as a dipole transmitter.
 3. The apparatus of claim1, wherein the multi-directional transmitter is configured to operate asa monopole transmitter.
 4. The apparatus of claim 1, wherein the patterncontrol module controls the transmitter to output a first portion of thepattern on a first electrode of the plurality of transmission electrodesand a second portion of the pattern on a second electrode oftransmission the plurality of electrodes, each transmission occurringsimultaneously.
 5. The apparatus of claim 1, wherein the pattern controlmodule controls the transmitter to output a first portion of the patternon a first electrode of the plurality of transmission electrodes and asecond portion of the pattern on a second electrode of the plurality oftransmission electrodes, each transmission occurring sequentially. 6.The apparatus of claim 2, wherein the plurality of transmissionelectrodes represent a high voltage potential and the apparatuscomprises a common electrode that represent a low voltage potentialwherein current flows through the liquid environment from the highvoltage electrodes to the low voltage electrode and wherein theapparatus includes a conductance control component for altering theconductance to control the current flow to produce a unique currentsignature.
 7. The apparatus of claim 1, wherein each of the plurality oftransmission electrodes is coupled to an antenna.
 8. The apparatus ofclaim 7, wherein each of the antennas is linear.
 9. The apparatus ofclaim 7, wherein each of the antennas is non-linear.
 10. The apparatusof claim 1, wherein the control unit is configured to sequentiallytransmit portions of the pattern and wherein the portions are bits. 11.The apparatus of claim 1, wherein the unit is rendered operational uponthe apparatus coming into contact with a target site fluid present at atarget site.
 12. A system for marking the occurrence of an event, thesystem comprising: an electrical pattern production unit, wherein theelectrical pattern production unit comprises: a logical control unit forproducing an identifiable electrical pattern; a multi-directionaltransmitter comprising a plurality of output conductors and electricallycoupled to the logical control unit, and wherein each of the pluralityof output conductors is capable of emanating the pattern; and a sealedstructure, wherein the plurality of output conductors are distributedabout the structure and the logical control unit is contained in thestructure; and wherein the logical control unit controls electricalcurrent conducted through the liquid environment from the plurality oftransmission electrodes of the multi-directional transmitter to emanatethe pattern in at least two directions using at least two of theplurality of output conductors, and wherein the multi-directionaltransmitter is configured to operate as a monopole transmitter whenemanating the pattern in the at least two directions using the at leasttwo of the plurality of output conductors; and wherein the plurality oftransmission electrodes comprise a first, second and third emanatingelements and the unit is configured to produce the pattern using thefollowing sequence of emanating elements: the first and second emanatingelements; the second and third emanating elements; and the third andfirst emanating elements; and a receiver for detecting the patternproduced by the logical control unit to record the occurrence of theevent.
 13. The system of claim 12, wherein said receiver is an in vivoreceiver.
 14. The system of claim 12, wherein said receiver is an exvivo receiver.